Liquid dosage forms of imatinib

ABSTRACT

Imatinib is approved and marketed in solid oral dosage forms which may be dispersed in water or apple juice for patients having swallowing difficulty. Dispersion of Imatinib solid dosage forms in apple juice may increase palatability and patient compliance but apple juice may not be available all the time for administration. Further, dispersion of Imatinib solid oral dosage forms may not administer correct and consistent dose of medicine every time. The present invention therefore provides liquid dosage forms of Imatinib which correctly and consistently administers correct dose of drug to the patients.

FIELD OF THE INVENTION

The present invention relates, in general, to the pharmaceutical field,and more precisely it relates to the liquid dosage forms ofprotein-tyrosine kinase inhibitor such as Imatinib or pharmaceuticallyacceptable salt thereof. In particular, the present invention relates toready to use, liquid dosage forms of Imatinib or pharmaceuticallyacceptable salt thereof and to the processes for the preparationthereof.

BACKGROUND OF THE INVENTION

Imatinib, chemically known asN-(4-methyl-3-[4-(pyridin-3-yl)pyrimidin-2-yl]amino)phenyl)-4-[(4-methylpiperazin-1-yl)methyl]benzamidehaving an empirical formula C₂₉H₃₁N₇O and a molecular weight of 493.6gm/mol has a following structural formula:

Imatinib mesylate is a protein-tyrosine kinase inhibitor; it inhibitsthe abnormal functioning Bcr-Abl tyrosine kinase, which is produced bythe Philadelphia chromosome abnormality, found in chronic myeloidleukemia (CML). Imatinib inhibits cell proliferation and inducesapoptosis (programmed cell death) in the Bcr-Abl cell lines and in theleukemic cells generated by CML. Imatinib also inhibits proliferationand induces apoptosis in gastrointestinal stromal tumor (GIST) cells,which express an activating c-kit mutation. More recently, the drug hasbeen approved for the treatment of mesenchymal cell neoplasms of theintestinal tract.

It has now been discovered that Imatinib mesylate can be used as atreatment for patients suffering from hepatic fibrosis based on itsability to downregulate stellate cell activation in culture and in vivo.

Imatinib mesylate is well absorbed after oral administration with Cmaxachieved within 2-4 hours post-dose. It was also reported that meanabsolute bioavailability is 98%. Biotransformation of Imatinib mesylateis via hepatic metabolism and cytochrome P450 enzymes (especiallyCYP3A4). Imatinib mesylate is converted to its main circulating activemetabolite, a N-desmethylated piperazine derivative. This derivative, invitro, has potency similar to Imatinib mesylate and comprises about 15%of the AUC (area under the curve) for Imatinib mesylate. When imatinibmesylate is orally administered, the elimination half-lives of Imatinibmesylate and its major active metabolite, the N-desmethyl derivative,are approximately 18 and 40 hours, respectively and the time to reachpeak concentration is 2 to 4 hours.

Imatinib mesylate is presently available as tablet form of 100 mg and400 mg. The approved dosage range for imatinib mesylate in the treatmentof CML is 400 mg to 800 mg (400 mg twice a day) and 600 mg per day forgastrointestinal stromal tumors (GIST).

It was reported that amounts of imatinib mesylate effective to treathepatic fibrosis would broadly range between about 50 mg and about 600mg per day and preferably between about 50 mg and about 200 mg per dayadministered orally.

Prior art reveals that Imatinib or pharmaceutically acceptable saltthereof has been formulated into solid dosage forms. Liquid dosage formsof Imatinib or pharmaceutically acceptable salt thereof are not muchexplored by the formulation scientists. The prior arts mentioned in theforthcoming paragraphs are incorporated herein by references for all thepurposes.

EP 1895984 and US 20060275372 describes a stable nanoparticulatecomposition of imatinib mesylate, or a salt thereof and at least onesurface stabilizer. EP 2009008 discloses a pharmaceutical compositioncomprising imatinib mesylate having less than about 0.09% area HPLCpercent units of desmethyl-imatinib mesylate and at least onepharmaceutically acceptable cxcipients. EP 2120877 and US 2010087444describes a solid dispersion of imatinib mesylate comprising imatinibmesylate and a pharmaceutically acceptable carrier, wherein said carrieris a cellulose derivative.

US 2016143850 and EP 3019159 describes a granulate composition ofimatinib mesylate comprising of imatinib mesylate, binder and ofdisintegrant.

US 2008119479 discloses a pharmaceutical composition which comprisesZD6474 or a pharmaceutically acceptable salt thereof, and imatinib, inassociation with a pharmaceutically acceptable cxcipient or carrier. EP2782560 and US 2015125534 discloses a pharmaceutical powder formulationcomprising granules of a tyrosine kinase inhibitor, wherein the granulesof the tyrosine kinase inhibitor are coated with an enteric coating,wherein the tyrosine kinase inhibitor is present in an amount of up to23% by weight based on the total weight of the pharmaceutical powderformulation.

WO 2006132930 discloses a pharmaceutical combination comprising apyrimidylaminobenzamide compound and Imatinib.

U.S. Pat. No. 8,653,093. U.S. Pat. No. 7,767,688. EP 1893213 and WO2006132930 discloses a medicament for the treatment of gastrointestinalstromal tumours by use of a pharmaceutical combination comprising of4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamideor a pharmaceutically acceptable salt thereof, and imatinib or apharmaceutically acceptable salt thereof.

WO 2014041551 (hereinafter referred as '551 publication) discloses oralaqueous solution comprising Imatinib or pharmaceutically acceptable acidaddition salts or polymorphs thereof, process for preparing suchsolution and their use in the treatment of chronic myeloid leukemia,gastrointestinal stromal tumors. The specification of '551 publicationteaches oral aqueous solution which essentially comprises viscosityregulating agent that is used to stabilize the active ingredient (i.e.Imatinib mesylate) or increase the viscosity of the oral solution.Preferred viscosity regulating agents according to the specification of'551 publication are polyvinyl pyrrolidone and hypromellose. Suchpreferred viscosity regulating agent has not been used in the oralsolutions of the present invention being the first major differencebetween the present invention and the invention disclosed in thespecification of '551 publication. Thus, the stability achieved by theoral solution of the present invention and results provided in thepresent specification are without using (i) viscosity regulating agentspreferred in the specification of '551 publication, and (ii) anyadditional stabilizing agent.

Further, the specification of '551 publication does not providestability results of the oral solution prepared therein. Upon readingthe specification of '551 publication, a skilled person cannot have anidea regarding stability and shelf life of the Imatinib oral solutiondisclosed therein. What the specification provides is mere statementthat “the formulation is found to be stable throughout the period of thestability study.” (See page 19; lines 13-14) The specification of '551does not define what should be considered as “stable” and also that whatis the period of“stability study”. Therefore it is difficult for askilled person to envisage stability of the oral solution disclosed inthe specification of '551 publication.

Another major difference between the invention disclosed in thespecification of '551 publication and the present invention is that theoral solution of Imatinib disclosed in the specification of '551publication is shown supra-bioavailable (which means the AUC and Cmax ofthe oral solution disclosed in the specification of '551 publication ishigher than either the acceptable values or values shown by Imatinibtablets) when tested in rats against Imatinib tablets, whereas the oralsolution of the present invention has been found bioequivalent (whichmeans all the pharmacokinetic parameters such as AUC, Cmax is within theacceptable limits when compared with Imatinib tablets) to the marketedGleevec (Imatinib) tablets during clinical studies in humans. Further,supra-bioavailability may not be advantageous as sometimes it may leadto toxicity and/or other side effects. Furthermore, just because theoral solution disclosed in the specification of '551 publication issupra-bioavailable in rats does not necessarily mean that it can beadministered to humans. Thus, the oral solution of Imatinib according tothe present invention is ready to use for human administration.

Currently available preparations of Imatinib are solid oral preparationse.g. tablets, and capsules. These preparations have their owndisadvantages and limitations, for example they are not suitable for alltypes of patient populations. Therefore there is an existing need forliquid dosage forms of Imatinib having prolonged stability andpalatability.

Compared to the conventional tablets and capsules, oral liquid dosageforms including solutions, syrups, suspensions, elixirs, andconcentrates offer unique advantages to many patients. For example,liquids may provide better patient compliance for those with swallowingdifficulties and better dosage control versus a fixed tablet dose.Hence, liquid dosage forms are generally formulated for use in geriatricand pediatric patients. However, there are also a number of “challenges”surrounding the formulation and development of these forms.

Children generally reject taking medicine which does not have afavorable shape, taste, flavor, etc. However, if a child who needs totake a medicine, rejects taking it, he might never recover from hiscondition. When a child is unable to take medicine orally, it isintravenously administered, and he and his caregivers then mayexperience stress. Syrups and suspensions are considered as favorabletypes of dosage forms in which to orally administer medicine to infantsand children. However, they may have disadvantages such as solubility, abad taste, portability problems or required refrigerator storage.Palatability is one of the main elements of patient acceptability of anoral pediatric medicine. Palatability is defined as the overallappreciation of an oral medicinal product in relation to its smell,taste, aftertaste and feeling in the mouth. Design of the formulation ofan oral pediatric medicine should be considered together with itspalatability.

According to Gleevec® prescribing information, Gleevec® tablets can bedissolved in water or apple juice for patients having swallowingdifficulty but in any treatment an important consideration is to ensurethat the patient receives the correct dose of medicine. Administrationof Gleevec® tablets by dissolving in water or apple juice may notadminister correct and consistent dose every time. Disadvantagesassociated with such an administration is that (i) Gleevec tablets takemuch longer time to get dispersed in water or apple juice and (ii) itleaves behind lots of residues in the container after administrationresulting into the administration of incorrect dose. Further, Imatinibhas bitter taste and administration with apple juice may mask its tasteand increase the palatability and patient compliance. But apple juice orany other flavored beverage may not be available all the time whileadministering a drug to the patient. It may therefore happen thatpatients have to take medicines with water which creates cloyingsensation in their mouth. Ii will therefore be desirable to haveImatinib containing dosages in liquid forms which also containsweeteners and flavors which makes such dosage forms palatable and morepatient compliant. Further, liquid dosage forms provide assurance ofdosage uniformity upon administration to patients and eliminatesdifficulty of administration. Liquid dosage forms can also providephysicians more flexibility in designing dosage regimens for patients.Such liquid dosage forms are advantageous to pediatric patients,geriatric patients and those patients who are unable to take oraltherapy.

OBJECTS OF THE INVENTION

Because of their liquid character, liquid dosage forms represent anideal dosage form for patients who have difficulty swallowing tablets orcapsules. This factor is of particular importance in administration ofdrugs to children and aged patients. Further, as mentioned above,administration of Imatinib tablets by dispersing in water or apple juiceis also not preferred because of administration of incorrect andinconsistent dose every time. It is therefore principal object of thepresent invention to provide liquid dosage forms of Imatinib orpharmaceutically acceptable salt thereof. The liquid dosage forms of thepresent invention are useful for administering to pediatric, geriatricpatients and other patients who are unable to take solid oral therapy.The liquid dosage forms according to the present invention includeliquids, liquid dispersions, suspensions, solutions, emulsions, sprays,spot-on, syrups, elixirs, drops, gels, solution-gels, concentrates andthe like.

Liquid dosage forms are designed as ready to use liquids and as powderfor reconstitution into liquid orals like syrups, solutions, suspensionsand emulsions. Powder for reconstitution may require skills & expertiseand needs to be prepared by a healthcare provider and may not beprepared by the patient or caregiver. The reconstitution process mayalso he a time consuming process and the patient cannot be benefited bythe immediate dose of Imatinib as and when required. In such asituation, ready to use, liquid dosage forms of Imatinib may be veryuseful and the patients can be given required doses immediately usingready to use, liquid dosage forms of Imatinib. Therefore, a yet anotherobject of the present invention is to provide ready to use, liquiddosage forms of Imatinib or pharmaceutically acceptable salt thereof.

The solution dosage form can be a viable alternative for patients whohave problems in swallowing the tablet or capsule dosage form. Itprovides assurance of dosage uniformity upon administration to patientsand eliminates difficulty of administration. A solution can also providephysicians more flexibility in designing dosage regimens for patients.Imatinib solution dosage form is suitable for administration to bothpediatric and geriatric patients while also compensating for a goodorganoleptic properties and remaining suitably stable. Hence, thedevelopment of a liquid formulation is therefore desirable since itoffers improved patient compliance. A yet another object of the presentinvention is therefore to develop solution dosage forms of Imatinib orpharmaceutically acceptable salt thereof. The solution dosage formsaccording to the present invention comprises Imatinib orpharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients or additives selected from thegroup comprising of vehicles, solvents/co-solvents, solubilizers,surfactants, pH adjusting agents and/or pH1 modifying agents and/orbuffering agents or any combination thereof. The solution dosage formsaccording to the present invention may further comprise one or moreagents selected from the group comprising of preservatives, sweeteningagents, flavoring agents and coloring agents or any combination thereof.

Suspensions possess certain advantages over other liquid dosage forms.Some drugs are insoluble in all acceptable media and must, therefore, beadministered as a tablet, capsule, or as a suspension. In addition,disagreeable tastes can be masked by a suspension of the drug or aderivative of the drug. Drugs in suspension are chemically more stablethan in solution. In another object, the present invention thereforeprovides suspension dosage forms of imatinib or pharmaceuticallyacceptable salt thereof. The suspension dosage forms according to thepresent invention comprises lmatinib or pharmaceutically acceptable saltthereof and one or more pharmaceutically acceptable excipients oradditives selected from the group comprising of vehicles,solvents/co-solvents, solubilizers, suspending agents/thickeningagents/viscosity modifying agents, anti-foaming agents, anti-cakingagents, wetting agents, surfactants, pH adjusting agents and/or pHmodifying agents and/or buffering agents or any combination thereof. Thesuspension dosage forms according to the present invention may furthercomprise one or more agents selected from the group comprising ofpreservatives, sweetening agents, flavoring agents and coloring agentsor any combination thereof.

A yet another object of the present invention is to provide liquiddosage forms of Imatinib or pharmaceutically acceptable salt thereofhaving palatability, prolonged stability and improved and/or comparablepharmacokinetic profile or bioavailability when compared to the known ormarketed Imatinib formulations. The liquid dosage forms of the presentinvention comprise sweetener(s) and flavoring agent(s) which masks thebitter taste of Imatinib and provides pleasant taste.

A yet another object of the present invention is to provide process forthe preparation of liquid dosage forms of Imatinib or pharmaceuticallyacceptable salt thereof.

A yet another object of the present invention is to provide use of theliquid dosage forms of the present invention in the manufacture of amedicament.

A yet another object of the present invention is to provide liquiddosage forms of the present invention for use as a medicament.

A yet another object of the present invention is to provide method forthe treatment of a disease or disorder that can be treated by inhibitingprotein-tyrosine kinase comprising administering to a patient, such ashuman, an effective dosage amount of a liquid dosage form comprisingImatinib or pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients or additives as disclosed anddescribed herein. A yet another object of the present invention is toprovide method for the treatment of a tumor disease or cancer diseasecomprising administering to a patient, such as human, an effectivedosage amount of a liquid dosage form comprising Imatinib orpharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients or additives as disclosed anddescribed herein. A yet another object of the present invention is toprovide method for the treatment of at least one disease or conditionselected from the group comprising of chronic myeloid leukemia, acutelymphoblastic leukemia, myeldysplastic diseases, mycloproliferativediseases, aggressive systemic mastocytosis, hypereosinophilic syndromeand/or chronic eosinophilic leukemia, unresectable, recurrent and/ormetastatic dermatofibrosarcoma protuberans, and unresectable and/ormetastatic malignant gastrointestinal stromal tumors comprisingadministering to a patient, such as human, an effective dosage amount ofa liquid dosage form comprising Imatinib or pharmaceutically acceptablesalt thereof and one or more pharmaceutically acceptable excipients oradditives as disclosed and described herein.

A yet another object of the present invention is to use the liquiddosage forms of the present invention for the treatment of a disease ordisorder that can be treated by inhibiting protein-tyrosine kinase. Ayet another object of the present invention is to use the liquid dosageforms of the present invention for the treatment of a tumor disease or acancer disease. A yet another object of the present invention is to usethe liquid dosage forms of the present invention for the treatment of atleast one diseases or condition selected from the group comprising ofchronic myeloid leukemia, acute lymphoblastic leukemia, myelodysplasticdiseases, myeloproliferative diseases, aggressive systemic mastocytosis,hypereosinophilic syndrome and/or chronic cosinophilic leukemia,unrescctablc, recurrent and/or metastatic dermatofibrosarcomaprotuberans, and unresectable and/or metastatic malignantgastrointestinal stromal tumors.

DETAILED DESCRIPTION OF THE INVENTION

Characteristics of an active drug are of major concern in developing anoral liquid dosage formulation. The major challenges in developing oralliquid dosage forms are (i) the stability of a drug in aqueous solution,suspension or emulsion. (ii) the solubility of a drug at the requiredlevel, and (iii) an acceptable taste and (iv) to be bioavailable whentaken orally. It is the effective use of excipients, which allowsformulators overcome these challenges Additionally, an excipient'scompatibility with a drug in the solid state cannot infer the samecompatibility in liquid dosage.

The decision to develop a solution, syrup or a suspension of a drug isinfluenced by many factors like solubility, particle size and thedesired release profile of the drug and properties of the base vehiclelike surface tension, viscosity, boiling point, and specific heat ofsolution, all of which may be affected in various ways. In case of clearliquids, lack of solubility of the drug in the base vehicle may demandthe need for miscible pharmaceutical co-solvents. Similarly, a misciblesolvent may be needed to decrease the solubility of the drug in aprimary vehicle in formulating a suspension.

The therapeutic utility of drugs involves the application of dosageforms/delivery systems, which serve as carrier systems together withseveral excipients to deliver the active therapeutic agent to the siteof action. Suspensions are an important class of pharmaceutical dosageforms that may be given by many routes, including oral, topical,parenteral, and also used in the eye for ophthalmic purposes.Surprisingly, large proportions of new drug candidates that are emergingare predominantly water insoluble and, therefore, demonstrate poorbioavailability in the solution dosage form. While suspensions present aviable formulation option for many drugs, particularly for waterinsoluble, hydrophobic drug substances, there are certain criteria thata well-formulated suspension should meet.

The suspension dosage form has long been used for poorly soluble activeingredients for various therapeutic indications. Development of stablesuspensions over the shelf life of the drug product continues to be achallenge on many fronts. Drugs from suspension formulations typicallyexhibit an improved bioavailability when compared to the same drugformulated as a tablet or capsule.

A good understanding of the fundamentals of disperse systems isessential in the development of a suitable pharmaceutical suspension.The development of a suspension dosage form follows a very complicatedpath. The selection of the proper excipients (surfactants, viscosityimparting agents etc.) is important. The particle size distribution inthe finished drug product dosage form is a critical parameter thatsignificantly impacts the bioavailability and pharmacokinetics of theproduct.

The advantages of suspension dosage forms include effective dispensingof hydrophobic drugs; avoidance of the use of co-solvents; masking ofunpleasant taste of certain ingredients; offering resistance todegradation of drugs due to hydrolysis, oxidation or microbial activity;easy swallowing for young or elderly patients; and efficientintramuscular depot therapy. In addition, when compared to solutiondosage forms, relatively higher concentration of drugs can beincorporated into suspension products. To date, numerous theories havebeen introduced and successfully used to explain the unique behavior ofsuspension preparations.

An important consideration in any treatment regime is to ensure that thepatient receives the correct dose of medicine. For many patients andmany drugs there is an acceptable dose window that allows fixed-dosemedicines to be used to treat patients with a wide range of body weightswithout the need to precisely adjust the dose. However, there are othergroups of patients where the “fixed-unit-dose” model may not beappropriate, depending on the drug's therapeutic index andpharmacokinetics. e.g. pediatric patients, geriatric patients, patientswith severe renal insufficiency and patients with severe hepaticinsufficiency. Oral solid unit dose forms. e.g. tablets and capsules,are not convenient under such circumstances since they are fixedstrength unit dose forms. In contrast, oral liquid dose forms do havethe in-built flexibility that allows the dose to be tailored to thepatients' needs.

Where the drug is sufficiently soluble, a solution dosage form, e.g. asimple mixture, may be used. But not all drugs are sufficiently solubleto allow suitable strength solution medicines to be developed andmanufactured with an acceptable shelf-life. In such cases, analternative approach could be to develop a stable aqueous suspensionthat will allow consistent dosing of the patient. Pharmaceuticalsuspensions have several advantages and disadvantages when compared toother dosage forms. Since suspensions are liquids, dose adjustment forpatients with renal or hepatic impairment, or for pediatric or geriatricpatients, may be more straightforward. This is an oversimplification ofthe development of a dosing strategy for a drug candidate. There aremany other details that must be considered for a formulation developmentproject to be successful, but it does provide a simple overview of someof the issues.

The suspension must be physically stable (no appreciable settling) for asufficient time, chemically stable over the required time (shelf-life),possess a viscosity that allows it to be used for its intended purpose,be easily reconstituted by shaking, and be acceptable in use to thepatient care-giver or other user.

Some materials may possess a combination of properties useful in theformulation and manufacture of stable, elegant pharmaceuticalsuspensions. Formulation scientists need to consider the totality ofproperties possessed by a particular excipient. Even though it is beingadded for one particular characteristic, the other properties will stillbe present, and will still influence the formulation.

Many of the recently discovered active pharmaceutical ingredients arequite hydrophobic with limited solubility. They may also be quitedistasteful. Other drugs may also have quite a high chemical degradationprecluding them to be administered as aqueous solutions, and in thiscase, it may be possible to synthesize an insoluble derivative. In othercases, some drugs are required to be present in the gastrointestinaltract or in the pre-corneal pocket with long residence time. For suchdrugs, a suspension is an ideal delivery system as it provides betterchemical stability and larger surface area and is often morebioavailable than aqueous solutions, tablets, and capsules.

Formulation of an elegant, stable, preserved, safe, and effectivesuspension is a technically challenging task compared aqueous solutions,tablets, and capsules. Pharmaceutical suspensions are thermodynamicallyunstable systems. Thus, preparation of such systems is often associatedwith problems of physical stability, content uniformity, sedimentation,caking, re-suspendibility, and crystal growth. Furthermore, issuesrelated to the masking of bitter taste and undesirable odor of thepharmaceutical ingredient must be taken into consideration.

Some desirable attributes of a suspension are described as follows,

1. It should be safe, effective, stable, and pharmaceutically elegantduring the shelf life of the product.2. The drug should not have a quick sedimentation rate. Furthermore, itshould re-suspend easily upon shaking and it must not cake.3. Physical attributes such as particle size, particle sizedistribution, viscosity should remain fairly uniform throughout theshelf life of the product.4. Its viscosity must promote free and uniform flow from the container.The product must be appropriately substantive that it spreads freelyover the affected area.5. Re-suspension should produce a homogeneous mix of drug particles suchthat there is a content uniformity with each dose.

A quick means to identify whether or not a drug may be more suitable forsolution or suspension is to overlap the pH-stability profile with thepH-solubility profile. This overlap creates a window, which may suggestwhich dosage form might be most desirable and subsequently the type ofexcipients needed.

Oral liquid formulation needs a meticulous blend of ingredients toperform various functions like wetting and solubilization, stabilizationand to impart suitable color, taste and viscosity. The blend should becompatible, non-reactive and stable. The common excipients generallyrequired for any liquid formulation are vehicles (base), viscositybuilders, stabilizers, preservatives, colors and flavors. In addition,solubilizers are required in case of clear liquids, suspending agentsare needed for suspensions and emulsifying agents for emulsions.

Imatinib is an inhibitor of protein-tyrosine kinase and commerciallyavailable as tablets (Gleevec®) in the United States since 2003 and isindicated for the treatment of chronic myelogenous leukemia (CML) andacute lymphocytic leukemia (ALL) that are Philadelphiachromosome-positive (Ph+) and certain types of gastrointestinal stromaltumors (GIST), systemic mastocytosis, and myelodysplastic syndrome.According to Gleevec prescribing information, Gleevec® tablets can bedissolved in water or apple juice for patients having swallowingdifficulty but in any treatment an important consideration is to ensurethat the patient receives the correct dose of medicine. Administrationof Gleevec® tablets by dissolving in water or apple juice may notadminister correct and consistent dose every time. In the principalaspects, the present invention therefore provides liquid dosage forms ofImatinib or pharmaceutically acceptable salt thereof.

The liquid dosage forms according to the present invention include, butnot limited to, liquids, liquid dispersions, suspensions, solutions,emulsions, ointments, creams, sprays, spot-on, syrups, elixirs, drops,gels, solution-gels, concentrates and the like. Such liquid dosage formscan be prepared using appropriate one or more pharmaceuticallyacceptable excipients or additives. Such excipients or additives may beknown to those skilled in the art.

The solution dosage form can be a viable alternative for patients whohave problems in swallowing the tablet or capsule dosage form. Itprovides assurance of dosage uniformity upon administration to patientsand eliminates difficulty of administration.

A solution can also provide physicians more flexibility in designingdosage regimens for patients. Imatinib solution dosage form is suitablefor administration to both pediatric and geriatric patients while alsocompensating for a good organoleptic properties and remaining suitablystable. Hence, the development of a liquid formulation is thereforedesirable since it offers improved patient compliance. In one of thefurther aspects, the present invention therefore provides solutiondosage forms of Imatinib or pharmaceutically acceptable salt thereof.

Suspensions possess certain advantages over other liquid dosage forms.Some drugs are insoluble in all acceptable media and must, therefore, beadministered as a tablet, capsule, or as a suspension. In addition,disagreeable tastes can be masked by a suspension of the drug or aderivative of the drug. Drugs in suspension are chemically more stablethan in solution. Therefore, in one of the further aspects, the presentinvention provides suspension dosage forms of Imatinib orpharmaceutically acceptable salt thereof.

Liquid dosage forms are designed as ready to use liquids and as powderfor reconstitution into liquid orals like syrups, solutions, suspensionsand emulsions. Powder for reconstitution may require skills & expertiseand needs to be prepared by a healthcare provider and may not beprepared by the patient or caregiver. The reconstitution process mayalso be a time consuming process and the patient cannot be benefited bythe immediate dose of Imatinib as and when required. In such asituation, ready to use, liquid dosage forms of Imatinib may be veryuseful and the patients can be given required doses immediately usingready to use, liquid dosage forms of Imatinib. In one of the furtheraspects, the present invention therefore provides ready to use, liquiddosage forms of Imatinib or pharmaceutically acceptable salt thereof.

Liquid dosage forms of an active drug can be prepared using one or morepharmaceutically acceptable excipients or additives suitable for thepreparation of liquid dosage forms. In one of the further aspects, thepresent invention provides liquid dosage forms of Imatinib orpharmaceutically acceptable salt thereof and one or more excipients oradditives suitable for preparing liquid dosage forms.

The term “pharmaceutically acceptable excipients or additives” as usedherein refers to such pharmaceutically acceptable excipients which areknown to those skilled in the all for the purposes of preparing liquiddosage forms of the present invention. Such pharmaceutically acceptableexcipients, without limitation include, vehicles, solvents/co-solvents,solubilizers, solubility enhancing agents, tonicity agents,permeation/penetration enhancers, mucoadhesives, suspendingagents/thickening agents/viscosity modifying agents, bulkingagents/auxiliary suspending agents, wetting agents, anti-foaming agents,anti-caking agents, stabilizing agents, anti-oxidants, chelating agents,buffering agents/pH modifying agents/pH adjusting agents, surfactants,preservatives, sweetening agents, flavouring agents and the like or anycombination thereof. Such pharmaceutically acceptable excipients can beused in an amount which provides the liquid dosage forms of the presentinvention desired property for which they are intended or desired touse.

In one of the further aspects, the present invention provides liquiddosage forms of Imatinib in the form of solution dosage forms comprisingImatinib or pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients or additives selected from thegroup comprising of vehicles, solvents/co-solvents and/or solubilizers.pH adjusting agents and/or pH modifying agents and/or buffering agentsor any combination thereof. One or more surfactants may also be added inthe solution dosage forms of the present invention.

In one of the further aspects, the present invention provides liquiddosage forms of Imatinib in the form of suspension dosage formscomprising Imatinib or pharmaceutically acceptable salt thereof and oneor more pharmaceutically acceptable excipients or additives selectedfrom the group comprising of vehicles, solvents/co-solvents and/orsolubilizers, suspending agents/thickening agents/viscosity modifyingagents, anti-foaming agents, surfactants, antioxidants, pH adjustingagents and/or pH modifying agents and/or buffering agents or anycombination thereof. One or more anti-caking agents may also be added inthe suspension dosage forms of the present invention.

Microbiological contamination presents a significant health hazard inoral liquids. Therefore, the use of preservatives become inevitable toprevent the growth of microorganisms during the product's manufactureand shelf life. Therefore, in one of the further aspects, the liquiddosage forms of the present invention may also comprise anti-microbialagents or preserving agents or preservatives.

Increase in the palatability of the drug formulations increases thepatient compliance and patient acceptability towards the drug. In one ofthe further aspects, the present invention therefore provides palatableliquid dosage forms comprising Imatinib or pharmaceutically acceptablesalt thereof and at least one or both selected fromsweeteners/sweetening agents and flavouring agents.

The liquid dosage forms according to the present invention, withoutlimitation include, aqueous dosage forms, alcoholic and/orhydro-alcoholic dosage forms and non-aqueous dosage forms. Aqueousdosage forms according to the present invention may also comprise one ormore non-aqueous and/or organic solvents.

In certain aspects, the present invention provides liquid dosage formsof Imatinib in the form of suspensions comprising Imatinib orpharmaceutically acceptable salt thereof, vehicle(s),solvent(s)/co-solvent(s), solubilizer(s), suspending agent(s)/thickeningagent(s)/viscosity modifying agent(s), preservative(s), anti-foamingagent(s), wetting agent(s), surfactant(s), pH adjusting agent(s)/pHmodifier(s) or buffering agent(s) or both, sweetener(s) and flavoringagent(s).

In certain aspects, the present invention provides liquid dosage formsof Imatinib in the form of solutions comprising Imatinib orpharmaceutically acceptable salt thereof, vehicle(s),solvent(s)/co-solvent(s), solubilizer(s), preservative(s),surfactant(s), pH adjusting agent(s)/pH modifier(s) or bufferingagent(s) or both, sweetener(s) and flavoring agent(s).

In one of the further aspects, the liquid dosage forms of the inventionmay be administered orally or via the oral cavity. The liquid dosageforms of the present invention may also be administered transmucosally,sublingually, via the buccal cavity, via mucosal membranes and/orthrough the gastrointestinal tract. In one of the further aspects, theliquid dosage forms of the present invention may be administered viapulmonary, intravenous, rectal, opththalmic, colonic, parenteral,intracisternal, intravaginal, intraperitoneal, local, or topicaladministration.

In some of the aspects, the liquid dosage forms of the present inventioncan be given using oral syringe to those patients who cannot takemedicine through mouth e.g. patients who have undergone surgery.

In some of the aspects, the liquid dosage forms of the present inventionare in the form of spray and may be administered by oral route or nasalroute. Sprays are known by various names such as aerosol sprays, liquidpump sprays, or activated mists etc.

In some of the aspects, the liquid dosage forms of the present inventionare in the form of immediate release dosage forms or modified releasedosage forms, such as extended release, controlled release, sustainedrelease, prolonged release and delayed release. In some of the aspects,the liquid dosage forms comprise Imatinib or pharmaceutically acceptablesalt thereof one or more suitable excipients or additives for thepreparation of modified release dosage forms such as rate controllingpolymers.

The liquid dosage forms of the present invention may also be prepared byreconstitution of dry powder in suitable diluent or media such as water.The dry powder for reconstitution may be in the form of immediaterelease forms and comprise Imatinib or pharmaceutically acceptable saltthereof and one or more suitable excipients selected form the groupcomprising of fillers, binders, diluents, disintegrants, pore formers,lubricants, glidants, sweeteners, stabilizing agents, antioxidants,flavoring agents, suspending agents/thickening agents/viscositymodifying agents, surfactants, preservatives and plasticizers. The drypowder for reconstitution may also be in the form of modified releaseforms and comprise modified release pellets, granules or particles. Suchmodified release pellets, granules or particles comprise one or moresuitable excipients such as rate controlling polymers.

In one of the further aspects, the liquid dosage forms of the inventionare suitable for administration to all types of patients' population. Inparticular, liquid dosage forms of the invention are suitable forpediatric and geriatric patients. The liquid dosage forms of theinvention are also useful for the patients who are unable to take solidoral therapy.

In some of the aspects, the pH of the liquid dosage forms of the presentinvention is between about 2.0 and about 11.0. In some of the aspects,the pH of the liquid dosage forms of the present invention is betweenabout 2.0 and about 7.0. In some of the aspects, the pH of the liquiddosage forms of the present invention is between about 3.0 and about9.0. In some of the aspects, the pH of the liquid dosage forms of thepresent invention is between about 4.0 and about 8.0. In some of theaspects, the pH of the liquid dosage forms of the present invention isbetween about 5.0 and about 7.0. In some of the aspects, the pH of theliquid dosage forms of the present invention is between about 5.5 andabout 6.5. In some of the aspects, the pH of the liquid dosage forms ofthe present invention is between about 3.5 and about 5.0.

In one of the further aspects, the pH of the liquid dosage forms of thepresent invention is such that prevents the formation of degradants inundesired amounts and provides the liquid dosage forms of the presentinvention increased stability when stored under storage conditions. Inone of the non-limiting aspects, the pH of the liquid dosage forms ofthe present invention which prevents the formation of degradants inundesired amounts and provides the liquid dosage forms of the presentinvention increased stability when stored under storage conditions is inthe range from about 2.0 to about 7.0.

In one of the further aspects, the liquid dosage forms of the presentinvention are stable for prolonged time when stored under storageconditions. The term “storage conditions” as used herein withoutlimitation include typical storage conditions such as 2° C.-8° C., 40°C.±2° C./75±5% RH, 30° C.±2° C./65±5% RH, 25° C.±2° C./40±5% RH, 25°C.±2° C./60±5% RH, 40° C.±2° C.±2° C./NMT 25% RH (NMT=not more than) andaccelerated conditions such as 40° C.±2° C./75±5% RH. The term“prolonged time” as used herein indicates that the liquid dosage formsof the present invention are stable for at least 1 month, at least 3months, at least 6 months or at least 12 months when stored understorage conditions.

As used herein, the terms “stable” or “stability” encompass anycharacteristic of the liquid dosage forms which may be affected bystorage conditions including, without limitation, potency, totalimpurities, degradation products, specific optical rotation, opticalpurity, water content, appearance, viscosity, sterility, and colour andclarity. The storage conditions which may affect stability include, forexample, duration of storage, temperature, humidity, and/or lightexposure.

The term “degradant”, “impurity”, “degradation impurity” and “relatedsubstance” as used herein represents the same meaning and can be usedinterchangeably.

In some of the aspects of the present invention. “stable” or “storagestable”, or “stability” when used with reference to the liquid dosageforms of the present invention or when used “stable liquid dosage forms”or “stability of the liquid dosage forms” all these terms/phrases referto dosage forms of the present invention which retain at least about90%, or at least about 95%, or at least about 96%, or at least about98%, of the labelled concentration of Imatinib or salt thereof containedin the said dosage form after storage under typical and/or acceleratedconditions. In further aspects, stable liquid dosage forms or stabilityof the liquid dosage forms refer to less than about 15% (area percent),or less than about 10% (area percent), or less than about 7% (areapercent), or less than about 5% (area percent), or less than about 2%(area percent) of Imatinib-related impurities are present after storageunder typical and/or accelerated conditions.

In some of the aspects, liquid dosage forms of the present inventioncontain no more than about 15% (area percent), or no more than about 10%(area percent), or no more than about 7% (area percent), or no more thanabout 5% (area percent), or no more than about 2% (area percent), or nomore than about 1% (area percent), or no more than about 0.5% (areapercent), or no more than about 0.2% (area percent), or no more thanabout 0.1% (area percent) any known or unknown single Imatinib-relatedimpurity or other impurity after storage under typical and/oraccelerated conditions.

In some of the aspects, liquid dosage forms of the present inventioncontain no more than about 15% (area percent), or no more than about 10%(area percent), or no more than about 7% (area percent), or no more thanabout 5% (area percent), or no more than about 2% (area percent), or nomore than about 1% (area percent), or no more than about 0.5% (areapercent), or no more than about 0.2% (area percent), or no more thanabout 0.1% (area percent) total Imatinib-related impurities or otherimpurities after storage under typical and/or accelerated conditions.

Methods for determining the stability of the liquid dosage forms of thepresent invention with respect to a given parameter are well-known tothose of skill in the art. For example, individual impurities and totalimpurities can be assessed by high-performance liquid chromatography(HPLC) or thin layer chromatography (TLC). Unless otherwise indicated tothe contrary, a percentage amount of any individual impurities(known/unknown), or total impurities reported herein in the liquiddosage forms are determined by a peak area percent method using HPLC.

The term “comprise/comprises/comprising” as used herein mean that otheringredients, steps, etc. are optionally present. When reference is madeherein to a method comprising two or more defined steps, the steps canbe carried in any order or simultaneously (except where the contextexcludes that possibility), and the method can include one or more stepswhich are carried out before any of the defined steps, between two ofthe defined steps, or after all of the defined steps (except where thecontext excludes that possibility).

The term “about,” as used herein, refers to any value which lies withinthe range defined by a variation of up to ±10% of the value.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of theclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.

All percentages mentioned herein, unless otherwise indicated, are on aw/v basis. i.e. percentage ingredient (active/inactive) present byweight in the total volume of the liquid dosage form.

In accordance with the methods of use and administration of medicinalproducts, packaging materials, closures and containers vary a great dealand have to meet a wide variety of different requirements. The liquiddosage forms of the present invention may be packaged within any type ofpharmaceutically-acceptable package, containers, pumps, bottles withspray pump, bottles with dropper assembly, bottles, collapsible tubes,glass ampoules, stoppered vials, pre-filled syringes, low-densitypolyethylene (LDPE), high-density polyethylene (HDPE), polyolefin,polypropylene containers/bottles depending upon the quantity of thefinal dosage form. The bottles or containers without limitation includeclear/transparent/opaque or amber colored glass bottles or containersand clear/transparent/opaque or amber colored plastic bottles orcontainers made from polyethylene, polyamide, polycarbonate, acrylicmultipolymers, polypropylene, polyethylene terephthalate, polyvinylchloride, polystyrene and the like. Depending upon the type of thecontainers or bottles, closures may have different shapes and sizes. Theclosure of the packaging material may be made from polyethylene,polyamide, polycarbonate, acrylic multipolymers, polypropylene,polyethylene tercphthalate, polyvinyl chloride, polystyrene and thelike.

Liquid dosage forms of the present invention may be packaged in asterile single use bottle/container that contains a unit dose foradministration to a patient. Suitable bottles/containers may containvolumes between 1-10 ml, 10-20 ml, 20-40 ml, and 40-100 ml, and evenmore. The container may typically comprise Imatinib or pharmaceuticallyacceptable salt thereof in an amount of between 10-40 mg, between 40-80mg, between 80-130 mg, and even more. Thus, it may also be noted thatthe container may be a multi-use container (i.e., retains at least onemore unit dose after a first unit dose is dispensed).

Following embodiments of the invention describe suitable excipientswhich may be used to prepare liquid dosage forms of the presentinvention. It is in no way the intention of the presentinventor(s)/applicant(s) to limit the scope of the liquid dosage formsof the present invention by the description of following embodiments.Described embodiments are for illustrative purpose only and a skilledperson may use other excipients from the same or different classes aswell which may provide liquid dosage forms of the present invention sameor improved physico-chemical properties, palatability, stability and thelike and retain or increase patients' acceptability towards the therapy.Such other excipients, classes of excipients and compositions resultedtherefrom are also part of the present invention and covered within thescope of the present invention.

Vehicles may be used in the liquid compositions of the presentinvention. Vehicles are the liquid bases that carry drugs and otherexcipients in dissolved or dispersed state. Vehicles may be aqueous ornon-aqueous or mixture thereof. Non-aqueous solvents/co-solvents mayalso be added in the liquid compositions of the present invention toincrease the solubility of poorly soluble substances and enhance thechemical stability of a drug. Suitable solvents/co-solvents,solubilizers or vehicles, that may be employed, in the liquidcompositions of the invention include, but are not limited to,dichloromethane, acetonitrile, ethyl acetate, acetone, propylenecarbonate, water, glycerine, coconut fatty acid diethanolamide, mediumand/or long chain fatty acids or glycerides, monoglycerides,diglycerides, triglycerides, structured triglycerides, soybean oil,peanut oil, corn oil, corn oil monoglycerides, corn oil diglycerides,corn oil triglycerides, polyethylene glycol,caprylocaproylmacroglycerides, caproyl 90, propylene glycol,polyoxyethylenesorbitan fatty acid esters, polyoxyethylene castor oilderivatives, castor oil, cottonseed oil, olive oil, safflower oil,peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid,methanol, ethanol, isopropyl alcohol, butanol, acetone, methyl isobutylketone, methyl ethyl ketone and the like or any combinations thereof.

In some of the non-limiting aspects of the present invention, thenon-aqueous solvent is glycerin. In some of the further aspects, theglycerin may also act as a stabilizing agent when the liquid dosageforms of the present invention comprise water as vehicle and providedesired stability when stored under storage conditions. In some of thefurther aspects, the amount of glycerin used to provide desiredstability to the liquid dosage forms of the present invention is atleast about 25% or more, at least about 30% or more, at least about 40%or more, at least about 50% or more, or at least about 60% or more.

Wetting agents as used herein are routinely used in pharmaceuticalformulations, especially in liquid dosage forms to create a homogeneousdispersion of solid particles in a liquid vehicle. This process can bechallenging due to a layer of adsorbed air on the particle's surface.Hence, even particles with a high density may float on the surface ofthe liquid until the air phase is displaced completely. The use of awetting agent allows removal of adsorbed air and easy penetration of theliquid vehicle into pores of the particle in a short period of time. Foran aqueous vehicle, alcohol, glycerin, and PG are frequently used tofacilitate the removal of adsorbed air from the surface of particles.Whereas for a non-aqueous liquid vehicle, mineral oil is commonly usedas a wetting agent. Non-limiting examples of wetting agents areBenzalkonium chloride, Benzcehonium chloride, Cetylpyridinium chloride,Docusate sodium, Nonoxynol 9, Octoxynol, Poloxamer, Poloxamer 124.Poloxamer 188, 237, 338, 407, Polyoxyl 35 castor oil, Polyoxyl 40hydrogenated castor oil. Polyoxyl 10 oleyl ether. Polyoxyl 20cetylstearyl ether. Polyoxyl 40 stearate. Polysorbate 20, Polysorbate40, Polysorbate 60, Polysorbate 80, Sodium lauryl sulfate. Sorbitanmonolaurate, Sorbitan monooleate. Sorbitan monopalmitate. Sorbitanmonostearate, Tyloxapol and the like or any combinations thereof.

Solubility enhancing agents may include, but are not limited to,DL-methionine, caffeine, nicotinamide, vanillin, benzyl alcohol, ethanoland diethylene glycol monoethyl ether and the like or combinationsthereof.

Stabilizing agents may include, but are not limited to, sodiummetabisulphite, sodium bisulphite, ethylene diamine tetraacetic acid(EDTA) or salts thereof, ascorbic acid and the like or combinationsthereof.

Penetration/permeation enhancers may include, but are not limited to,nicotinamide, caffeine, peppermint oil, sodium glycocholate,phospholipids, alkyl saccharides, aprotinin, benzalkonium chloride,ceramides, cetylpyridinium chloride, chitosan,chitosan-4-thiobutylamidine, cyclodextrins, dextran sulfate, dodecylazacycloheptyl-2-ketone, ether lipids (plasmologens), glycerol,glycosylated sphingosines, lauric acid, 23-lauryl ether,lysophosphatidyl choline, menthol, methoxysalicylate, phosphatidylcholine, 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine,polycarbophil cysteine, poly-L-arginine, polyoxyethylene,polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol. EDTA,sodium deoxycholate, sodium glycocholate, sodium glycodeoxycholate,sodiun lauryl sulfate, sodium salicylate, sodium taurocholate, sodiumtaurodeoxycholate, sodium taurodihydrofusidate, sphingolipids, sterolsand the like or combinations thereof.

Mucoadhesives and/or suspending agents may also be added in thecompositions of the present invention. Examples of suitablemucoadhesives include, but are not limited to, hydroxypropyl cellulose,gelatin, crosslinked polyacrylic acid, polymethacrylic acid,polyhydroxyethyl methacrylic acid, hydroxypropyl methyl cellulose,polyethylene glycol, sodium carboxymethyl cellulose, hyaluronic acid,chitosan, polycarbophil, pectin, xanthan gum, alginate, copolymers ofdextran, polyacrylamide, acacia, copolymer of caprolactone and ethyleneoxide, carbopol 934, tragacanth, eudragit and the like or combinationsthereof.

Suspending agents may be natural or synthetic gums or gum derivatives orcompounds which swell in the presence of aqueous media.

Stabilizing agents may include, but are not limited to, sodiummetabisulphite, sodium bisulphite, ethylene diamine tetraacetic acid(EDTA) or salts thereof, ascorbic acid and the like or combinationsthereof.

The pH of an oral liquid formulation is a key point in many regards.Control of the formulation pH, could prevent large changes duringstorage. Therefore, most formulations utilize a buffer to controlpotential changes in the solution pH. The amount of buffer capacityneeded is generally between 0.01 and 0.1 M, and a concentration between0.05 and 0.5 M is usually sufficient. The selection of a suitable buffershould be based on (i) Whether the acid-base forms are listed for use inoral liquids, (ii) The stability of the drug and excipients in thebuffer, and (iii) The compatibility between the buffer and container. Acombination of buffers can also be used to gain a wider range of pHcompared to the individual buffer alone. However, not all buffers aresuitable for use in oral liquids. For example, a boric acid buffer maybe used for optical and IV delivery but not in oral liquids because ofits toxicity. The stabilizing effect of buffers that have multiplecharged species in solution could also determine the potential reactionbetween excipients and API. For example, buffers that use carbonates,citrate, tartrate, and various phosphate salts may precipitate withcalcium ions by forming sparingly soluble salts. However, thisprecipitation is dependent upon the solution pH. The activity ofphosphate ions may be lowered due to interactions with other solutioncomponents.

There are a number of factors that may also affect the solution pH suchas temperature, ionic strength, dilution, and the amount and type ofco-solvents present. For example, the pH of acetate buffers is known toincrease with temperature, whereas the pH of boric acid buffersdecreases with temperature. Finally, the drug in solution may itself actas a buffer. If the drug is a weak electrolyte, such as salicylic acidor ephedrine, the addition of base or acid, respectively, will create asystem in which the drug can act as a buffer.

One of the most crucial factors involved in formulating a pharmaceuticalsuspension is the selection of an appropriate suspending agent.Suspending agents impart viscosity, and thus retard particlesedimentation. Other factors considered in the selection of theappropriate agent include desired rheological property, suspendingability in the system, chemical compatibility with other excipients, pHstability, length of time to hydrate, batch-to-batch reproducibility,and cost. Non-limiting examples of pH adjusting agents/modifiers andbuffers are Acetic acid, Adipic acid, Ammonium carbonate, Ammoniumhydroxide, Ammonium phosphate. Boric acid, Citric acid, Diethanolamine,Fumaric acid. Hydrochloric acid, Malic acid. Nitric acid. Propionicacid. Potassium acetate. Potassium bicarbonate. Potassium chloride,Potassium citrate, Potassium metaphosphate. Potassium phosphate, Sodiumacetate. Sodium bicarbonate. Sodium borate, Sodium carbonate. Sodiumchloride. Sodium citrate, Sodium glycolate, Sodium hydroxide, Sodiumlactate, Sodium phosphate, Sodium proprionate, Succinic acid, Sulfuricacid. Tartaric acid. Triethylamine, Triethanolamine, Tromethamine.Trolamine and the like or any combinations thereof.

In some of the aspects of the present invention, the term “bufferingagent” or “buffering agents” may also interchangeably be used with theterms “pH adjusting agent or pH adjusting agents” or “pH modifying agentor pH modifying agents” and vice versa and represents the same meaning.

Suspending agents can be classified into cellulose derivatives, clays,natural gums, and synthetic gums. In many cases, these excipients areused in combination. There are many water soluble hydrocolloids that canact as suspending agents in the formulation of pharmaceuticalsuspensions. They can be of natural, semi-synthetic or synthetic origin.Non-limiting examples of suspending agents are Acacia. Agar, Alginicacid. Carbomer. Carmellose sodium. Dextrin, Gelatin. Veegum or Gelwhite. Gellan gum, Sodium alginate. Methylcellulose, Hydroxyethylcellulose, Hydroxypropyl cellulose. Hydroxypropylmethyl cellulose,Hydroxypropyl starch, Hypromellose. Maltodextrin. Methylcellulose,Modified starch. Pectin, Poloxamer, Polycarbophil, Polyethylene glycol.Polyvinyl acetate, Poly (vinyl alcohol), Potassium alginate. Polyvinylpyrrolidone. Pregelatinized starch. Propylene glycol alginate. Sodiumalginate. Carboxymethyl cellulose or an alkali metal salt thereof,Microcrysalline cellulose, gum Arabic, Karaya gum, Sterculia gum.Tragacanth, Xanthangumn, Bentonite, Carageenan. Guar gum. Colloidalsilicon dioxide and the like or any combinations thereof.

In some of the non-limiting aspects of the present invention, thesuspending agent is present in the liquid dosage forms of the presentinvention at a concentration which helps to achieve desired dissolutionprofile of the suspension dosage forms of the present invention.

Microbiological contamination presents a significant health hazard inoral liquids. Therefore, the use of preservatives become inevitable toprevent the growth of microorganisms during the product's manufactureand shelf life, although it may be most desirable to develop a“preservative-free” formulation to address the increasing concerns aboutthe biological activity of these compounds. Most formulations requiresome kind of preservative to ensure no microbial growth.

The majority of preservatives are bacteriostatic rather thanbacteriocidal, and consists of both acid and nonacid types. Among theacidic types are phenol, chlorocresol, 9-phenyl phenol, alkyl esters ofpara-hydroxybenzoic acid, benzoic acid, boric acid, and sorbic acid, andtheir respective salts. Therefore, the pH of solution, and the pKa ofthe preservative need to be carefully evaluated prior to selecting apreservative for a formulation. Neutral preservatives includechlorobutanol, benzyl alcohol, and beta-phenylethyl alcohol. Underalkaline conditions, it is generally regarded that microbial growth isinsignificant and at these pH values, the need for a preservative is notgenerally recommended.

Many preservatives listed in the FDA inactive ingredient guide forliquid dosage forms. Unfortunately, many of them are not recommended foruse in oral liquids and hence the choice of an acceptable preservativefor an oral liquid formulation is limited. In addition, the solubilityof many preservatives in aqueous system may not be high enough foreffective antimicrobial activity. Additionally, it is essential tounderstand that bacteriostatic agents like para hydroxyl hbenzoic acidscan partition between organic and aqueous phases in a heterogenousliquid formulations in such a way that their activity is significantlyreduced. Non-limiting examples of preservatives are Alcohol, Ethanol,Chlorobutanol, Phenoxyethanol, Potassium benzoate, Benzyl alcohol.Benzoic acid, Potassium sorbate. Sorbic acid, Benzalkonium chloride,Benzethonium chloride, Cetrimonium bromide, Cetylpyridinium chloride.Bronopol, Chlorbutol, Chlorocresol, Cresol Butylparaben, Methylparaben.Propylparaben. Ethylparaben. Phenol, Thymol. Phenylethanol. Sodiumbenzoate, Antimicrobial solvents like Propylene glycol. Glycerin.Chloroform and the like or any combinations thereof. In addition, someformulation ingredients like nonionic surfactants, quaternary ammoniumcompounds, gelatin, ferric salts, calcium salts and salts of heavymetals, including silver, lead, and mercury prevent microbial growth.

In some of the non-limiting aspects, the liquid dosage forms of thepresent invention comprise one or more than one preservatives. In someof the further non-limiting aspects, the liquid dosage forms of thepresent invention comprise combination of two preservatives. In some ofthe further non-limiting aspects of the present invention, thepreservatives are present in the liquid dosage forms of the presentinvention at a concentration which helps to prevent microbial growth inthe liquid dosage forms when stored for prolonged time under storageconditions.

Antioxidants can be compounds that can reduce a drug that has beenoxidized, or compounds that are more readily oxidized than the agentsthey are to protect (oxygen scavengers). Many of the lipid-solubleantioxidants act as scavengers. Antioxidants can also act as chainterminators, reacting with free radicals in solution to stop thefree-radical propagation cycle. Mixtures of chelating agents andantioxidants are often used because there appears to be a synergisticeffect. This occurs because many of the agents act at differing steps inthe oxidative process.

Some substances prone to oxidation include unsaturated oils/fats,compounds with aldehyde or phenolic groups, colors, flavors, sweeteners,plastics and rubbers, the latter being used in containers for products.Oxidation may manifest as products with an unpleasant odour, taste,appearance, precipitation, discoloration or even a slight loss ofactivity. The term rancidity refers to many typical off-flavors thatresult from autoxidation of unsaturated fatty acids that are present inoils and fats, and it affects many oils and fats. The distinct rancidodour may result from short-chain, volatile monomers resulting from thecleavage of the longer chain, less volatile oils and fats. Non-limitingexamples of anti-oxidants are α-Tocopherol acetate. Ascorbic acid.Erythorbic acid. Butylated hydroxytoluene (BHT), d-α-Tocopherol natural.Monothioglycerol, Sodium bisulfite, Sodium sulfite. Sodiummetabisulfite. Potassium metabisulfite, Acetone sodium bisulfite.Ascorbyl palmitate, Cysteine, d-α-tocopherol synthetic.Nordihydroguaiaretic acid, Sodium formaldehyde sulfoxylate, Sodiumthiosulfate. Acetylcysteine, Ascorbyl palmitate, Butylatedhydroxyanisole (BHA), Cysteine hydrochloride, Dithiothreitol, Propylgallate, Thiourea and the like or any combinations thereof.

In some instances, there are insufficient drug particles in a unit doseof suspension to make a pharmaceutically elegant suspension. This isparticularly true for the more highly active drugs, where the unit doseis small. Under such circumstances, the formulator will need to add moreparticles to improve the appearance of the final product, and also tohelp stabilize the suspension. To serve this purpose, bulking agents,also known as auxiliary suspending agents are used. Non-limitingexamples of bulking agents are Calcium carbonate. Calcium hydroxide.Cellulose, Crospovidone, Dibasic calcium phosphate, Magnesium carbonate.Magnesium hydroxide, Microcrystalline cellulose, Silica (silicondioxide), Titanium dioxide and the like or any combinations thereof.

Many different materials are capable of adsorbing onto the suspendedparticles, e.g. natural gums, cellulosics and non-ionic surfactants.However, not all of them are able to act as protective colloids andprovide steric hindrance to caking at a sufficiently low concentration.High levels of surfactants, for example, can increase gastro-intestinalmotility. Higher molecular weight gums and cellulosics may also cause anunacceptable increase in the viscosity of the system. There are,however, certain polymers, or grades of polymers, that are capable ofacting as protective colloids at concentrations that do not markedlyincrease the viscosity of the system, or increase gut motility, etc.Such materials include poloxamers, lower molecular weight grades ofpovidone, and low molecular weight grades of some other hydrophiliccolloids.

Surfactant is a general name for materials that possess surfaceactivity; in solution they tend to orient at the surface of the liquid.There are several general classes of surfactants: anionic, cationic,amphoteric and non-ionic. Surfactants are amphiphilic molecules, i.e.part of the molecule is hydrophilic, and part is lipophilic. Thiscombination of the two opposite affinities in the same molecule causesthem to orient to the interface and thereby reduce the interfacialtension between the continuous and disperse phases, such as in emulsionsand suspensions. Ionic surfactants work primarily through electrostaticforces, whereas non-ionic surfactants work primarily through stericforces. Non-limiting examples of surfactants are Sodium lauryl sulfate.Docusate sodium, Cocamidopropyl amino betaine. Polyoxyethylene sorbitanfatty acid esters (Polysorbate, Tween®), Polyoxyethylene 15hydroxystearate (Macrogol 15 hydroxystearate, Solutol HS15@).Polyoxyethylene castor oil derivatives (Cremophor® EL, ELP, RH 40),Polyoxyethylene stearates (Myrj®). Sorbitan fatty acid esters (Span®),Polyoxyethylene alkyl ethers (Brij®), Polyoxyethylene nonylphenol ether(Nonoxynol®) and the like or any combinations thereof.

Anti-foaming agents may be used in the preparation of the liquidpharmaceutical compositions of the present invention to lower thesurface tension and cohesive binding of liquid phase. Non-limitingexamples of anti-foaming agents are simnethicone, organic phosphates,alcohols, paraffin oils, stearates, glycols and the like or anycombinations thereof.

Chelating agents, also known as sequestrants, are molecules that havethe ability to form stable complexes with metal ions, particularlydi-valent and tri-valent metal ions including trace metals and heavymetals. These metal ions are often implicated in API degradation byacting as catalysts, e.g. Mg²⁺ will catalyze both ester hydrolysis andthe Maillard interaction between primary or secondary amines andreducing sugars. Oxidative degradation is also often catalyzed by heavymetals. In addition, certain trace metals are required for microbialgrowth, and chelation (sequestration) to form complexes can help preventmicrobial growth and spoilage, and thus allow lower levels ofmicrobiocidal agents to be used. Non-limiting examples of chelatingagents are Calcium disodium edetate, Disodium edetate, Edetic acid (alsoknown as ethylenediaminetetraacetic acid/EDTA), Citric acid and the likeor any combinations thereof.

Palatability of oral medicines is an important factor in compliance.There are several components to palatability including flavor,mouth-feel and sweetness. Most patients prefer medicines that are nottoo bitter but may be slightly “tart” (acidic). Most APIs are bitter.However, for bitterness to develop, the drug must be sufficientlysoluble to interact with taste receptors on the tongue. For insolubleAPIs in the form of suspensions, components of the suspension are alsobitter, e.g. preservatives, or very salty, e.g. buffer systems. However,a slight saltiness and a slight bitterness are desirable forpalatability.

Traditionally, oral medicines were sweetened using Syrup (concentratedsucrose solution) or honey (contains fructose). However, these materialsare inadequate for the formulation of many products because they simplyare not able to adequately mask the very bitter taste of manypharmaceutical materials, including APIs and excipients. Severalalternative sweetening agents have been developed over the years tobetter mask unpleasant tastes in both processed foods andpharmaceuticals.

Several of the materials classified as sweetening agents are sugaralcohols (also known as polyhydric alcohols, polyols and hydrogenatedsugars). Several of the commonly used sweetening agents are ionic andhave the potential to interact with other components of the suspension.Some sweetening agents are more stable than others in aqueous solution.These will be important factors in the final selection of the sweeteningagent. Non-limiting examples of sweetening agents are Glucose,Sucralose, Trehalose, Fructose, Xylose, Dextrose, Galactose, Tagatose,Maltose, Sucrose, Glycerol, Dulcitol, Mannitol, Lactitol, Sorbitol,Xylitol, Saccharine or the corresponding sodium, potassium or calciumsalt, Cyclamate or the corresponding sodium or calcium salt. Aspartame,or Acesulfame or the potassium salt thereof. Dulcin or Ammoniumglycyrrhizinate, Alitame, Inulin, Isomalt, Ncohespcridindihydrochalcone. Thaumatin and the like or any combinations thereof.

Flavors are used to improve the palatability of oral medicines. Oneproblem that can arise with oral suspensions is that the suspension mayproduce a “cloying” sensation in the mouth. While this is not the sameas a bitter taste, it can nevertheless cause problems for the patientand affect compliance. This can be a particular problem with high levelsof inorganic components. Flavors can help reduce this “cloying” tasteand thereby improve palatability, and ultimately patient compliance.

There are many different flavors, and most flavors are complex mixturesof many components. Today most flavors are developed by specialistflavor houses, and typically the flavor is formulated for eachindividual application. Since flavor will be part of the suspensioncontinuous phase, it has the maximum potential for interaction, and someflavor components may cause stability issues (physical or chemical) forthe suspension. Flavor development and compounding is a specialistdiscipline. When deciding on which particular flavor is appropriate, theflavor specialist would benefit from knowledge of the other likelycomponents in the suspension, just as the formulation scientist wouldbenefit from knowledge of the components of the flavor.

Flavors can adsorb onto finely divided solids, thus reducing theireffectiveness. They can also be absorbed by packaging. Flavorpreferences vary with age, but the citrus flavors appear generallyacceptable to most age groups. Non-limiting examples of flavoring agentsare synthetic flavor oils and flavoring aromatics and/or natural oils,extracts from plants leaves, flowers, fruits, and so forth and the likeor any combinations thereof. These may include cinnamon oil, oil ofwintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus,thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitteralmonds, and cassia oil and the like or any combinations thereof. Alsouseful as flavors are vanilla, citrus oil, including lemon, orange,grape, lime and grapefruit, and fruit essences, including apple, banana,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot,and so forth and the like or any combinations thereof. Solid forms, suchas spray dried forms of flavoring agents, may also be useful in theliquid dosage forms disclosed herein.

Coloring agents may also be used in the preparation of the liquidcompositions of the present invention. Pharmaceutical colors come in twotypes; soluble dyes and insoluble pigments. For pharmaceuticalsuspensions intended for oral use, soluble dyes are often used; however,pigments may also be used and would be part of the disperse phase.Soluble dyes have the potential to interact with other components of theformulation.

In some of the aspects, the liquid dosage forms of the present inventionare non-caking liquid dosage forms. The term “non-caking” as used hereinmeans that the liquid dosage form has a smooth consistency and doesn'tcontain any caking or clumping particles, by visual inspection. Also,the liquid dosage form in accordance with the present invention does notcake or clump during manufacture, i.e., when mixed with excipients. Nordoes it cake or clump upon storage, even under relatively humidconditions, e.g., a relative humidity of about 75% or greater and whenstored for relatively long periods such as about 6 months or longer andeven at elevated temperatures of about 40° C. or greater, or at anycombination of such humidity, time and temperature parameters. Thus, theliquid dosage forms in accordance with the present invention will remainnon-caking during typical storage and use conditions. “Imatinib” as usedherein, unless the context requires otherwise, includes Imatinib, itspharmaceutically acceptable salts and chemical derivatives thereof suchas polymorphs, solvates, hydrates, anhydrous forms, amorphous forms,prodrugs, chelates, and complexes. “Imatinib” as used herein alsoincludes racemic or substantially pure forms.

In one of the further aspects. Imatinib or pharmaceutically acceptablesalt thereof used for the preparation of the liquid dosage forms of thepresent invention comprise particles of Imatinib or pharmaceuticallyacceptable salt thereof, wherein the d₉₀ of the particles of Imatinib orpharmaceutically acceptable salt thereof is less than about 1000 μm, orless than about 950 μm, or less than about 900 μm, or less than about850 μm, or less than about 800 μm, or less than about 750 μm, or lessthan about 700 μm, or less than about 650 μm, or less than about 600 μm,or less than about 550 μm, or less than about 500 μm, or less than about450 μm, or less than about 400 μm, or less than about 350 μm, or lessthan about 300 μm, or less than about 250 μm, or less than about 200 μm,or less than about 150 μm, or less than about 100 μm, or less than about90 μm, or less than about 80 μm, or less than about 70 μm, or less thanabout 60 μm, or less than about 50 μm, or less than about 40 μm, or lessthan about 30 μm, or less than about 20 μm, or less than about 10 μm, orless than about 5 μm, or less than about 2 μm, or less than about 1 μm,or less than about 0.5 μm.

In one of the further aspects, the liquid dosage forms of the presentinvention comprise particles of Imatinib or pharmaceutically acceptablesalt thereof, wherein the d₉₀ of the particles of Imatinib orpharmaceutically acceptable salt thereof is less than about 1000 μm, orless than about 950 μm, or less than about 900 μm, or less than about850 μm, or less than about 800 μm, or less than about 750 μm, or lessthan about 700 μm, or less than about 650 μm, or less than about 600 μm,or less than about 550 μm, or less than about 500 μm, or less than about450 μm, or less than about 400 μm, or less than about 350 μm, or lessthan about 300 μm, or less than about 250 μm, or less than about 200 μm,or less than about 150 μm, or less than about 100 μm, or less than about90 μm, or less than about 80 μm, or less than about 70 μm, or less thanabout 60 μm, or less than about 50 μm, or less than about 40 μm, or lessthan about 30 μm, or less than about 20 μm, or less than about 10 μm, orless than about 5 μm, or less than about 2 μm, or less than about 1 μm,or less than about 0.5 μm.

In one of the aspects, general formula of the liquid dosage formsaccording to the present invention may be provided as follows.

TABLE 1 General formula of liquid dosage forms of the present inventionQuantity (% w/v) Solution Suspension Sr No Ingredient dosage form dosageform 1 Irnatinib or pharmaceutically 0.01-25 0.01-25 acceptable saltthereof (active ingredient) 2 Suspending agent(s)/thickening — 0.01-10agent(s)/viscosity modifying agent(s) 3 Preservative(s) 0.01-10 0.01-104 Wetting agent(s) —   0-90 5 pH adjusting agent(s)/pH modifying Q.S. toQ.S. to agents adjust the pH adjust the pH 6 Buffering agent(s) Q.S. toQ.S. to adjust the pH adjust the pH 7 Solvent(s)/co-solvent(s) Q.S. Q.S.8 Solubilizer(s) Q.S. Q.S. 9 Anti-foaming agent(s) — 0.01-10 10Anti-caking agent(s) —   0-10 11 Antioxidant —   0-10 12 Surfactant(s)  0-10 0.01-10 13 Sweetening agent(s) 0.01-15 0.01-50 14 Flavoringagent(s) 0.01-5  0.01-5  15 Coloring agent(s)  0-2  0-2 16 Vehicle(s)Q.S. Q.S. Q.S. = Quantity Sufficient

Those who are skilled in the art will appreciate that different types ofliquid dosage forms as described herein can be prepared by usingsuitable excipients or additives known in the art. Thus, the name ofexcipients or additives and proportionate range thereof provided in theTable-1 is provided herein for the illustration purpose only and shouldnot be construed as the exact or the only scope of the presentinvention.

The liquid dosage forms of the present invention may be prepared usingsuitable excipients or additives in any suitable amount.

In one of the further aspects, the present invention provides processfor the preparation of the liquid dosage forms of Imatinib orpharmaceutically acceptable salt thereof.

Process-1: Preparation of Solution Dosage Forms

-   -   1. Add one or more sweetener(s) followed by one or more        preservative(s) in the suitable vehicle;    -   2. Add Imatinib or pharmaceutically acceptable salt thereof;    -   3. Add one or more buffering agent(s) to adjust the desired pH        followed by flavoring agent; and    -   4. Adjust the volume to the required quantity with vehicle.

Process-2: Preparation of Solution Dosage Forms

-   -   1. Add one or more solvent(s) followed by one or more        sweetener(s) and one or more preservative(s) in the suitable        vehicle;    -   2. Add Imatinib or pharmaceutically acceptable salt thereof;    -   3. Add one or more buffering agent(s) to adjust the desired pH        followed by flavoring agent; and    -   4. Adjust the volume to the required quantity with vehicle.

Process-3: Preparation of Suspension Dosage Forms

-   -   1. Add one or more preservative(s) followed by one or more        buffering agent(s) to adjust the desired pH in the suitable        vehicle;    -   2. Add one or more sweeteners) and flavoring agent followed by        one or more suitable solvent(s)/co-solvent(s) and/or one or more        solubilizer(s);    -   3. Add one or more suspending agent(s) followed by one or more        anti-foaming agent(s) and one or more surfactant(s);    -   4. Add Imatinib or pharmaceutically acceptable salt thereof; and    -   5. Adjust the volume to the required quantity with vehicle.

Process-4: Preparation of Suspension Dosage Forms

-   -   1. Add and mix one or more solubilizer(s) in the suitable        vehicle;    -   2. Add one or more suspending agent(s);    -   3. Add one or more antioxidant(s) and one or more sweetener(s)        dissolved in the suitable solvent(s) to step (2);    -   4. Add Imatinib or pharmaceutically acceptable salt thereof; and    -   5. Add flavoring agent and adjust the volume to the required        quantity with vehicle.

Those who are skilled in the art can understand that some variations inthe process described herein can be adopted. A skilled person may omituse of some pharmaceutical excipients as described herein above. Askilled person may also alternatively use some or all pharmaceuticalexcipients as described herein from the same excipient classes. Suchvariations are well within the scope of the present invention. A skilledperson can also change and/or omit steps of their sequences of theherein described process for the purposes of suitability and conveniencewhere one or more pharmaceutically acceptable excipients may or may notbe used without affecting and diminishing the quality andcharacteristics of the resulting product. Suchvariations/changes/omissions/additions are well within the scope of thepresent invention.

The liquid dosage forms of the present invention may also be preparedusing processes generally known to those skilled in the art. Theprocesses for the preparation of liquid dosage forms of the presentinvention may vary depending upon the final dosage form. e.g. solution,suspension, etc. The processes for the preparation of the liquid dosageforms of the present invention may comprise multiple steps. Such stepsmay include sequential addition of suitable excipients/additives. Suchsteps may also include physical processes for example mixing, stirring,agitation etc.

In one of the aspects, the liquid dosage forms of the present inventionare suitable for administration to a subject to treat or prevent adisease or condition. Preferably, the subject is a mammal. Morepreferably, the mammal is a human. Preferably, the disease or conditionis a disease or condition that is treatable by the administration ofImatinib or pharmaceutically acceptable salt thereof.

In one of the aspects, the present invention is directed to the methodfor the treatment of a disease or disorder or medical condition that canbe treated by inhibiting protein-tyrosine kinase comprisingadministering to a patient, such as human, an effective dosage amount ofa liquid dosage form comprising Imatinib or pharmaceutically acceptablesalt thereof and one or more pharmaceutically acceptable excipients oradditives as disclosed and described herein.

In one of the further aspects, the present invention is directed to themethod for the treatment of a tumor disease or cancer disease, includingwithout limitation, colon cancer, thyroid cancer, ovarian cancer, breastcancer, lung cancer (non-small cell lung cancer), head and neck cancer,uterine cancer, non-hodgkin lymphoma, blood cancer, skin cancer,prostate cancer, kidney cancer, rectal cancer, peritoneal cavity cancer,brain cancer, gastric cancer, metastatic cancer, colorectal cancer,pancreatic cancer, endometrial cancer, stomach cancer, gastrointestinalcancer, bladder cancer, and the like comprising administering to apatient, such as human, an effective dosage amount of a liquid dosageform comprising Imatinib or pharmaceutically acceptable salt thereof andone or more pharmaceutically acceptable excipients or additives asdisclosed and described herein.

In one of the further aspects, the present invention is directed to themethod for the treatment of at least one disease or condition selectedfrom the group comprising of chronic myeloid leukemia, acutelymphoblastic leukemia, myelodysplastic diseases, myeloproliferativediseases, aggressive systemic mastocytosis, hypereosinophilic syndromeand/or chronic cosinophilic leukemia, unresectable, recurrent and/ormetastatic dermatofibrosarcomna protuberans, and unresectable and/ormetastatic malignant gastrointestinal stromal tumors comprisingadministering to a patient, such as human, an effective dosage amount ofa liquid dosage form comprising Imatinib or pharmaceutically acceptablesalt thereof and one or more pharmaceutically acceptable excipicnts oradditives as disclosed and described herein.

“Effective dosage amount” as used herein with respect to, for exampleImatinib liquid dosage forms shall mean that dosage that provides thespecific pharmacological response for which Imatinib administered in asignificant number of subjects in need of such treatment. It isemphasized that “effective dosage amount”, administered to a particularsubject in a particular instance will not always be effective intreating the diseases described herein, even though such dosage isdeemed a “effective dosage amount” by those skilled in the art.

In one of the further aspects, the present invention is directed to useliquid dosage forms of the present invention for the treatment of adisease or disorder that can be treated by inhibiting protein-tyrosinekinase. In one of the further aspects, the present invention is directedto use liquid dosage forms of the present invention for the treatment ofa tumor disease or a cancer disease, including without limitation, coloncancer, thyroid cancer, ovarian cancer, breast cancer, lung cancer(non-small cell lung cancer), head and neck cancer, uterine cancer,non-hodgkin lymphoma, blood cancer, skin cancer, prostate cancer, kidneycancer, rectal cancer, peritoneal cavity cancer, brain cancer, gastriccancer, metastatic cancer, colorectal cancer, pancreatic cancer,endometrial cancer, stomach cancer, gastrointestinal cancer, bladdercancer, and the like.

In one of the further aspects, the present invention is directed to useliquid dosage forms of the present invention for the treatment of atleast one diseases or condition selected from the group comprising ofchronic myeloid leukemia, acute lymphoblastic leukemia, myelodysplasticdiseases, myeloproliferative diseases, aggressive systemic mastocytosis,hypereosinophilic syndrome and/or chronic eosinophilic leukemia,unresectable, recurrent and/or metastatic dermatofibrosarcomaprotuberans, and unresectable and/or metastatic malignantgastrointestinal stromal tumors.

The liquid dosage forms of the present invention are proposed to haveunexpectedly dramatic dissolution profiles. Rapid dissolution of anadministered active agent is preferable, as faster dissolution generallyleads to greater bioavailability and faster onset of action. To improvethe dissolution profile and bioavailability of Imatinib it would beuseful to increase Imatinib's dissolution so that it could attain alevel dose to 100% dissolution of the drug substance.

The liquid dosage forms of the present invention comprising Imatinib ora pharmaceutically acceptable salt thereof, exhibit improved orcomparable pharmacokinetic profiles as compared to known Imatinibcompositions, e.g. Gleevec®. For example, the Cmax and/or AUC of theliquid dosage forms of Imatinib of the present invention can be greaterthan or substantially equal to the Cmax and/or AUC for known Imatinibcompositions administered at the same dose. In addition, the Tmax of theliquid dosage forms of Imatinib of the present invention can be lowerthan or substantially equal to that obtained for a known Imatinibcompositions, administered at the same dose. In addition, combinationsof an improved or comparable Cmax, AUC and Tmax profile can be exhibitedby the liquid dosage forms of Imatinib of the invention, as compared toknown Imatinib compositions. In further aspects, the liquid dosage formsof Imatinib of the present invention may result in minimal differentabsorption levels when administered under fed as compared to fastingconditions.

In one of the aspects, a liquid dosage form comprising Imatinib orpharmaceutically acceptable salt thereof exhibits in comparativepharmacokinetic testing with an Imatinib marketed or known formulation,administered at the same dose, a Tmax not greater than about 90%, notgreater than about 80%, not greater than about 70%, not greater thanabout 60%, not greater than about 50%, not greater than about 30%, notgreater than about 25%, not greater than about 20%, not greater thanabout 15%, not greater than about 10%, or not greater than about 5% ofthe Tmax exhibited by the marketed or known Imatinib formulation.

In one of the further aspects, the liquid dosage form comprisingImatinib or pharmaceutically acceptable salt thereof exhibits incomparative pharmacokinetic testing with an Imatinib marketed or knownformulation, administered at the same dose, a Cmax which is at leastabout 50%, at least about 100%, or at least about 150%, greater than theCmax exhibited by the marketed or known Imatinib formulation. In one ofthe further aspects, the liquid dosage form comprising Imatinib orpharmaceutically acceptable salt thereof exhibits in comparativepharmacokinetic testing with an Imatinib marketed or known formulation,administered at the same dose, a Cmax which is in the range betweenabout 70% and about 150%.

In one of the further aspects, the liquid dosage form comprisingImatinib or pharmaceutically acceptable salt thereof exhibits incomparative pharmacokinetic testing with an Imatinib marketed or knownformulation, administered at the same dose, an AUC which is at leastabout 25%, at least about 50%, at least about 75%, at least about 100%,at least about 125%, at least about 150%, at least about 175%, or atleast about 200%, greater than the AUC exhibited by the marketed orknown Imatinib formulation. In one of the further aspects, the liquiddosage form comprising Imatinib or pharmaceutically acceptable saltthereof exhibits in comparative pharmacokinetic testing with an Imatinibmarketed or known formulation, administered at the same dose, an AUCwhich is in the range between about 80% and about 125%.

In one of the further aspects, the Tmax of Imatinib or salt thereof,when assayed in the plasma of the mammalian subject, is less than about6 to about 8 hours. In other aspects of the invention, the Tmax ofImatinib or salt thereof is less than about 6 hours, less than about 5hours, less than about 4 hours, less than about 3 hours, less than about2 hours, less than about 1 hour, or less than about 30 minutes afteradministration.

In some aspects, the liquid dosage forms of Imatinib of the presentinvention exhibit improved or comparable bioavailability as compared toknown Imatinib compositions, e.g. Gleevec®.

The present invention is further exemplified by the followingnon-limiting examples.

Best Mode of Carrying Out the Invention Examples

The liquid dosage forms of the present invention are explained in moredetail with reference to the following examples. These examples areprovided by way of illustration only and should not be construed as tolimit the scope or spirit of the claims in any manner.

Examples 1-4: Preparation of Solution Dosage Forms of Imatinib

TABLE 2 Examples of Irnatinib solution dosage forms (without glycerine)Example 1 Example 2 Example 3 Ingredients Quantity (mg/mL) Irnatinibmesylate 95.6 (free 95.6 (free 95.6 (free base = 80.0) base = 80.0) base= 80.0) Liquid maltitol 300.0 300.0 300.0 Methyl paraben 5.0 5.0 5.0Ethyl paraben 1.0 1.0 1.0 Citric acid Q.S. to Q.S. to Q.S. to desired pHdesired pH desired pH Sodium citrate Q.S. to Q.S. to Q.S. to desired pHdesired pH desired pH Strawberry flavour 0.1 0.1 0.1 Purified Water Q.S.to 1 mL Q.S. to 1 mL Q.S. to 1 mL Q.S. = Quantity sufficient; desired pH= between about 2.0 to about 7.0

Method or Preparation:

-   -   1. Take required quantity of water;    -   2. Dissolve required quantity of Methyl paraben and Ethyl        paraben in water. If required mixture may be heated to dissolve        Methyl paraben & Ethyl paraben and cooled down;    -   3. Add required quantity of Liquid maltitol and mix till get        homogenously mixed;    -   4. Add required quantity of Imatinib mesylate and mix till        completely dissolved;    -   5. Add Citric acid and Sodium citrate till desired pH is        attained;    -   6. Add required quantity of Strawberry flavour and mix till        completely dissolved; and    -   7. Make up the final desired volume with water.

TABLE 3 Stability data at different stability conditions of differentIrnatinib liquid compositions Single maximum Freeze-thaw study impurityTotal observation (Unknown) impurities (Freezer −10° C. Stabilitycondition pH NMT 0.2% NMT 1.0% to −20° C. for 2 days) Example 1 Initial3.48 0.02 0.57 Do not freeze but dark 3 M 40° C./25% RH 3.47 0.02 0.57brownish colour 3 M 25° C./40% RH 3.48 0.02 0.57 observed Example 2Initial 4.31 0.03 0.66 Product was 3 M 40° C./25% RH 4.31 0.03 0.69precipitated out 3 M 25° C./40% RH 4.27 0.03 0.66 Example 3 Initial 5.050.02 0.63 Product was 3 M 40° C./25% RH 5.05 0.03 0.65 precipitated out3 M 25° C./40% RH 5.03 0.03 0.62 NMT = Not more than

TABLE 4 Irnatinib solution dosage form (with glycerine) Example 4Ingredients Quantity (mg/mL) Irnatinib Mesylate 95.6 (free base = 80.0)Liquid maltitol 100.0 Glycerine 300.0 Sodium benzoate 0.2 Acesulfamepotassium 1.0 Citric acid monohydrate Q.S. to desired pH Strawberryflavour 0.1 Purified Water Q.S. to 1 mL Q.S. = Quantity sufficient;desired pH = between about 2.0 to about 7.0

TABLE 5 Irnatinib solution dosage form (with glycerine) Example-4Ingredients Quantity (mg/mL) Irnatinib mesylate    1-1000 Liquidmaltitol    0-500 Glycerin  250-800 Sodium benzoate    0-4.0 Acesulfamepotassium 0.01-10 Citric acid monohydrate Q.S. to desired pH Strawberryflavour 0.01-10 Purified water Q.S. to 1 mL Q.S. = Quantity sufficient;desired pH = from about 2.0 to about 7.0

Method of Preparation:

-   -   1. Take required quantity of purified water,    -   2. Add required quantity of Glycerin and mix till get        homogenously mixed;    -   3. Add required quantity of Liquid maltitol and mix till get        homogenously mixed;    -   4. Add required quantity of Sodium benzoate and mix till        completely dissolved;    -   5. Add required quantity of Acesulfame potassium and mix till        completely dissolved;    -   6. Add required quantity of Imatinib mesylate and mix till        completely dissolved;    -   7. Add Citric acid till desired pH is attained;    -   8. Add required quantity of Strawberry flavour and mix till        completely dissolved; and    -   9. Make up the final desired volume with Water.

TABLE 6 Stability data of Example 4 Single maximum impurity Total(Unknown) impurities Stability conditions pH NMT 0.2% NMT 1.0% Initial4.44 ND ND 40° C. ± 2° C./ 1 M 4.4 ND ND 25% RH 2 M 4.42 0.08 0.37 3 M4.64 0.06 (RRT 0.68) 0.63 6 M 4.6 0.07 (RRT 0.68) 0.69 25° C. ± 2° C./ 3M 4.55 0.06 (RRT 0.68) 0.55 40° ± 5% RH 6 M 4.55 0.06 (RRT 0.68) 0.57 ND= Not detected; NMT = Not more than

Example 5: Preparation of Suspension Dosage Form of Imatinib

TABLE 7 Example of Irnatinib suspension dosage form Quantity IngredientsFunction (mg/mL) Irnatinib or salt thereof Active ingredient 10-200Methyl paraben Preservative 0.1-5.0  Ethyl paraben Preservative 0.1-5.0 Xanthan gum Suspending agent/viscosity 0.1-10  builder Sorbitol solutionSweetener 0.1-500  Flavor Flavoring agent 0.1-50  Glycerin Solvent orco-solvent/  0-900 Wetting agent Disodium hydrogen phosphate Bufferingagent 1-50 dihydrate Sodium dihydrogen phosphate Buffering agent 1-50dihydrate Simethicone Anti-foaming agent 0.01-20   Polysorbate 80Surfactant/wetting agent 0-20 Purified water Vehicle Q.S. to 1 mL pH =between about 5.0 and about 8.5 Q.S. = Quantity sufficient

Method of Preparation:

-   -   1. Take required quantity of purified water;    -   2. Add methyl paraben and ethyl paraben and mix till get        dissolved, heating may be required, if necessary;    -   3. Add disodium, hydrogen phosphate dihydrate and sodium        dihydrogen phosphate dihydrate and mix till get dissolved;    -   4. Add sorbitol solution and flavor and mix till get dissolved;    -   5. Add glycerin and mix till get disperse d;    -   6. Add xanthan gum and mix till get dispersed;    -   7. Add simethicone and polysorbate 80 one by one and mix till        get dispersed;    -   8. Add Imatinib or salt thereof and mix to form homogenous        suspension; and    -   9. Adjust the final quantity with purified water.

Example 6: Preparation of Suspension Dosage Form of Imatinib

TABLE 8 Example of Irnatinib suspension dosage form Ingredients Quantity(mg/mL) Irnatinib or salt thereof 10-200 Ethanol (absolute)  0.001-0.5(mL) Butylated hydroxyl toluene (BHT) 0.01-1.0  Sucralose 0.1-25 Colloidal silicon dioxide 1-50 Flavor 0.1-25  Caprylocaproyl macrogo 8glycerides  1-200 Medium chain triglyceride Q.S. to 1 mL

Method of Preparation:

-   -   1. Add required quantity of medium chain triglyceride;    -   2. Add and mix caprylocaproyl macrogol 8 glycerides till get        uniformly dispersed;    -   3. Add and mix colloidal silicon dioxide till get uniformly        dispersed;    -   4. Add butylated hydroxy toluene (BHT) and sucralose dissolved        in ethanol mixture to step (3);    -   5. Add Imatinib or salt thereof; and    -   6. Add flavour and make up volume with medium chain        triglycerides.

Example 7: Bio-Equivalency Study of the Liquid Dosage Forms of thePresent Invention Prepared According to Example 4

The liquid dosage forms prepared according to Example 4 of the presentinvention were tested for its bio-equivalence against the referenceproduct, i.e. Gleevec® marketed tablets. The results of thebio-equivalence study shows that the liquid dosage forms of the presentinvention have improved and/or comparable pharmacokinetic profile and/orbioavailability when compared against the known Imatinib formulations.The results are summarized in the table below.

TABLE-9 Bio-equivalence study results Cmax Tmax AUC_(t) K_(ck) T_(1/2)AUC^(∞) AUC_ratio Mean 2170.34 2.81 34479.46 0.05 14.80 35929.20 96.00SD 800.16 0.98 13581.91 0.01 3.08 14259.21 0.29 Geometric GeometricLower Upper Mean Mean T/R Intra Inter confidence confidence Parameters(Test) (Reference) Ratio Power % CV % CV interval interval LAUCt33498.56 32140.21 104.23 100.00 13.74 36.48 98.15 110.68 LCmax 2149.352044.66 105.12 100.00 12.65 32.05 99.46 111.10

Example 8; Effect of Co-Solvent on the Liquid Dosage Form of the Present

9.56% Imatinib mesylate + 10% liquid maltitol + 20% glycerin + sodium9.56% Imatinib mesylate + 9.56% Imatinib mesylate + benzoate +acesulfame 10% liquid maltitol + 15% 10% liquid maltitol + 30%potassium + citric acid glycerin + 15% polyethylene polyethyleneglycol + monohydrate + strawberry glycol + sodium benzoate + sodiumbenzoate + flavor + water acesulfame potassium + acesulfame potassium +(the composition freezed citric acid monohydrate + citric acidmonohydrate + after 1^(st) cycle) strawberry flavor + water strawberryflavor + water Freeze (freezed) (freezed) thaw Freeze Freeze CompositionCycle III thaw thaw Test 60° C. (clear 60° C. Cycle III 60° C. Cycle IIIParameters Initial 7 days solution) Initial 7 days (freezed) Initial 7days (freezed) Related substances RRT-0.48 0.08% 0.09% 0.08% 0.09% 0.09%0.08% 0.09% 0.08% 0.07% RRT-0.59 0.03% 0.03% 0.03% 0.03% 0.03% 0.03%0.039% 0.03% — RRT-0.66 — — — — — — — — — RRT-0.67 — — — — — — — — —RRT-0.68 0.09% 0.07% 0.05% 0.09% 0.07% 0.01% 0.09% 0.08% 0.06% RRT-0.90— — — — 0.03% — — 0.03% — RRT-0.95 — — — — 0.03% — — 0.03% — RRT-1.200.12% 0.13% 0.12% 0.13% 0.13% 0.13% 0.13% 0.12% 0.11% RRT-1.43 — — — — —— — — — Total 0.34% 0.43% 0.40% 0.44% 0.49% 0.47% 0.40% 0.42% 0.37%impurities RRT = Relative retention time

From above data it can be concluded that the liquid dosage formcomprising only glycerin does not freeze after gone through freeze-thawcycles whereas the liquid dosage forms comprising (i) mixture ofglycerin and polyethylene glycol and (ii) only polyethylene glycol getsfreezed after gone through freeze-thaw cycle (for further data seeTable-10 below). Thus, glycerin is the preferredsolvent/co-solvent/solubilizer according to the present invention and atleast 25% or more glycerin is required to achieve optimum results.

Example-9: Free-Thaw Study and Super Accelerated Stability Study ofDifferent Liquid Dosage Forms Prepared

TABLE 10 Freeze-thaw cycle data of different liquid dosage forms Cycle 1Cycle 2 Cycle 3 Freezer Freezer Freezer (−10° C. (−10° C. (−10° C.Composition Batch No. to −20° C.) to −20° C.) to −20° C.) 9.56%Irnatinib mesylate + 10% liquid INBL2050 Slightly Clear solution- Clearsolution- maltitol + 20% glycerin + sodium freezed not freezed notfreezed benzoate + acesulfame potassium + citric acid monohydrate +strawberry flavor + water 9.56% Irnatinib mesylate + 10% liquid INBL2056Clear solution- Slightly Freezed maltitol + 15% glycerin + 15% notfreezed freezed polyethylene glycol + sodium benzoate + acesulfamepotassium + citric acid monohydrate + strawberry flavor + water 9.56%Irnatinib mesylate + 10% liquid INBL2059 Half bottle Half bottle Freezedmaltitol + 30% polyethylene glycol + freezed freezed sodium benzoate +acesulfame potassium + citric acid monohydrate + strawberry flavor +water

Example 10; Stability Comparison Between Test Formulations and ReferenceFormulation

TABLE-11 Super-accelerated stability study of test formulations andreference formulation 9.56% Imatinib mesylate + 20% Glycerin + 5%Polyvinyl pyrrolidone + 30% Sucrose + 9.56% Imatinib mesylate + 9.56%Imatinib mesylate +- sodium citrate dihydrate + l0% liquid maltitol +30% 10% liquid maltitol + 20% citric acid 1 hydrate + glycerin + sodiumbenzoate + glycerin + sodium benzoate Disodium edetate + acesulfamepotassium + + acesulfame potassium + sucralose + methyl citric acidmonohydrate + citric acid monohydrate + paraben + propyl paraben +strawberry flavor + water strawberry flavor + water sodium metabisulfite(Test formulation-1) (Test formulation-2) (Reference formulation)Composition 60° C. 60° C. 60° C. Test Initial 7 days Initial 7 daysInitial 7 days parameters Clear yellow Clear yellow Clear yellow Clearyellow Clear yellow Clear yellow Description solution solution solutionsolution solution solution Related substances RRT-0.00 — — — — — —RRT-0.09 — — — — — 0.03% RRT-0.10 — — — — 0.03% — RRT-0.33 — — — — 0.09%0.03% RRT-0.48 0.08% 0.09% 0.08% 0.09% 0.08% 0.09% RRT-0.49 — — — — — —RRT-0.59 0.03% 0.03% 0.03% 0.03% 0.03% 0.03% RRT-0.60 — — — — — —RRT-0.64 — — — — — — RRT-0.66 — — — — — — RRT-0.67 — 0.06% — — — 0.06%RRT-0.68 0.08% — 0.09% 0.07% 0.06% — RRT-0.69 — — — — — — RRT-0.70 — — —— 0.03% — RRT-0.84 — — — — — — RRT-0.90 — — — — — — RRT-0.95 — — — — — —RRT-1.20 0.12% 0.13% 0.12% 0.13% 0.12% 0.12% RRT-1.43 — — — — — — Total0.35% 0.41% 0.34% 0.43% 0.46% 0.45% impurities RRT = Relative retentiontime

The inventors of the present invention had prepared two formulations asTest Formulation-1 and Test Formulation-2 according to the presentinvention containing 30% glycerin and 20% glycerin respectively. Theinventors have compared these two test formulations with referenceformulation prepared according to WO 2014041551. From above table it canbe seen that both the test formulations have total impurities less thanthe reference formulation.

Example 11: Effect of Polyvinyl Pyrrolidone on Liquid Dosage Forms ofthe Present Invention

In order to find out the effect of viscosity regulating agent preferredin the specification of '551 publication (i.e. polyvinyl pyrrolidone) onthe liquid dosage forms of the present invention, the inventors of thepresent invention prepared two formulations, (i) with polyvinylpyrrolidone, and (ii) without polyvinyl pyrrolidone. These twoformulations were tested for its stability after seven days when keptunder super-accelerated conditions, i.e. 60° C. The results aresummarized in the table below.

9.36% Irnatinib mesylate + 10% 9.36% Irnatinib mesylate + 10% liquidmaltitol + 30% glycerin + 5% liquid maltitol + 30% glycerin + polyvinylpyrrolidone + sodium benzoate + acesulfame potassium + benzoate +acesulfame potassium + citric acid monohydrate + citric acidmonohydrate + strawberry strawberry flavor + water flavor + waterComposition 60° C. 6° C. Test parameters Initial 7 days Initial 7 daysDescription Clear yellow Clear yellow Clear yellow Dark brownishsolution solution solution solution Related substances RRT-0.48 0.08%0.09% 0.08% 0.09% RRT-0.59 0.03% 0.03% 0.03% 0.03% RRT-0.67 0.08% 0.06%0.08% 0.06% RRT-0.90 — — 0.09% 0.12% RRT-0.95 — — 0.06% 0.09% RRT-1.200.12% 0.13% 0.12% 0.13% RRT-1.43 — — — — Total impurities 0.35% 0.41%0.46% 0.58% RRT = Relative retention time

From above data, it can be seen that the appearance of the liquid dosageform without polyvinyl pyrrolidone does not change after one weekwhereas the appearance of the liquid dosage form with polyvinylpyrrolidone changes from clear yellow solution to dark brown solution.Further, it can also be seen that the percentage amount and numbers ofimpurities dramatically increases in the liquid dosage form withpolyvinyl pyrrolidone at initial stage and even after one week. Uponlooking at the stability study data, the liquid dosage form withoutpolyvinyl pyrrolidone found more stable than liquid dosage form withpolyvinyl pyrrolidone.

From the foregoing examples, it is apparent that the liquid dosage formsof Imatinib prepared according to the present invention are suitable foruse in the industry.

It should be understood that various changes and modifications to theembodiments described herein will be apparent to those skilled in theart. Such changes and modifications can be made without departing fromthe spirit and scope of the subject matter of the present invention andwithout diminishing its intended advantages. It is therefore intendedthat such changes and modifications be covered within the scope of thepresent invention.

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 26. A liquid dosage form of imatinib comprising: about0.01% w/v to about 25% w/v of imatinib mesylate; about 25% w/v to about60% w/v of glycerin; about 0.01% w/v to about 10% w/v of sodiumbenzoate; about 0.01% w/v to about 10% w/v of liquid maltitol; citricacid in a quantity sufficient to adjust the pH of the liquid dosage formto a desired pH; and water in a quantity sufficient to bring the finalvolume of the liquid dosage form to the desired volume.
 27. The liquiddosage form of claim 26, further comprising: about 0.01% w/v, to about5% w/v of acesulfame or the potassium salt thereof.
 28. The liquiddosage form of claim 26, further comprising about 0.01% w/v to about 5%w/v of strawberry flavour.
 29. The liquid dosage form of claim 26,wherein the pH is from about 2.0 to about 7.0.
 30. The liquid dosageform of claim 26 is ready to use oral solution.
 31. The liquid dosageform of claim 26 is stable liquid dosage form characterized in that anyindividual impurity present in the liquid dosage form is not more than2.0% and the total impurities present in the liquid dosage form are notmore than 5.0%.
 32. (canceled)
 33. The liquid dosage form of claim 26,wherein the dosage form has: (a) a C_(max) for imatinib, or a saltthereof, when assayed in the plasma of a mammalian subject followingadministration that is at least about 70% to about 143% greater than theC_(max) for an imatinib marketed or known formulation, administered atthe same dose; (b) an AUC for imatinib, or a salt thereof, when assayedin the plasma of a mammalian subject following administration that is atleast about 80% to about 125% greater than the AUC for an imatinibmarketed or known formulation, administered at the same dose; (c) aT_(max) for imatinib, or a salt thereof, when assayed in the plasma of amammalian subject following administration that is less than about 6hours to about 8 hours; or (d) any combination of (a), (b), and (c). 34.The liquid dosage form of claim 26 is packaged in the pharmaceuticallyacceptable packaging material selected from the group comprisingofcontainers, pumps, bottles with spray pump, bottles with dropperassembly, bottles, collapsible tubes, glass ampoules, stoppered vials,pre-filled syringes, wherein the bottles and containers are clear ortransparent or opaque or amber colored glass bottles and containers orclear or transparent or opaque or amber colored plastic bottles andcontainers made from polyethylene, low-density polyethylene,high-density polyethylene, polyamide, polyolefin, polycarbonate, acrylicmultipolymers, polypropylene, polyethylene terephthalate, polyvinylchloride, polystyrene.
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 41. A liquid dosage form ofimatinib comprising: about 0.01% w/v to about 25% w/v of imatinib or apharmaceutically acceptable salt thereof having d₉₀ between about 10 μmand about 200 μm; about 0.01% w/v to about 10% w/v of a suspendingagent; about 10% w/v to about 90% w/v of a solvent or co-solvent; and avehicle in a quantity sufficient to bring the final volume of the liquiddosage form to the desired volume.
 42. The liquid dosage form of claim41, wherein the suspending agent is selected from the group consistingof acacia, agar, alginic acid, carbomer, carmellose sodium, dextrin,gelatin, veegum or gel white, gellan gum, sodium alginate,methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxypropyl starch, hypromellose,maltodextrin, methylcellulose, modified starch, pectin, poloxamer,polycarbophil, polyethylene glycol, polyvinyl acetate, poly (vinylalcohol), potassium alginate, polyvinyl pyrrolidone, pregelatinizedstarch, propylene glycol alginate, sodium alginate, carboxymethylcellulose or an alkali metal salt thereof, microcrystalline cellulose,gum arabic, karaya gum, sterculia gum, tragacanth, xanthan gum,bentonite, carageenan, guar gum, colloidal silicon dioxide or anycombination thereof.
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 45. The liquid dosageform of claim 41, wherein the solvent or co-solvent is selected from thegroup consisting of dichloromethane, acetonitrile, ethyl acetate,acetone, propylene carbonate, glycerin, coconut fatty aciddiethanolamide, medium and/or long chain fatty acids or glycerides,monoglycerides, diglycerides, triglycerides, structured triglycerides,soyabean oil, peanut oil, corn oil, corn oil monoglycerides, corn oildiglycerides, corn oil triglycerides, polyethylene glycol,caprylocaproyl macrogol-8 glycerides, caproyl 90, propylene glycol,polyoxyethylenesorbitan fatty acid esters, polyoxyethylene castor oilderivatives, castor oil, cottonseed oil, olive oil, safflower oil,peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid,methanol, ethanol, isopropyl alcohol, butanol, acetone, methyl isobutylketone, methyl ethyl ketone or any combination thereof.
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 49. The liquid dosage form of claim 41,optionally comprising pH modifying agent or buffering agent selectedfrom the group consisting of acetic acid, adipic acid, ammoniumcarbonate, ammonium hydroxide, ammonium phosphate, boric acid, citricacid, diethanolamine, fumaric acid, hydrochloric acid, malic acid,nitric acid, propionic acid, potassium acetate, potassium bicarbonate,Potassium chloride, potassium citrate, potassium metaphosphate,potassium phosphate, sodium acetate, sodium bicarbonate, sodium borate,sodium carbonate, sodium chloride, sodium citrate, sodium glycolate,sodium hydroxide, sodium lactate, odium phosphate, sodium proprionate,succinic acid, sulfuric acid, tartaric acid, triethylamine,triethanolamine, tromethamine, trolamine or any combination thereof in aquantity sufficient to adjust the pH of the liquid dosage form to adesired pH.
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 52. The liquid dosage form ofclaim 41, further comprising one or more of the following, about 0.01%w/v to about 50% w/v of a sweetening agent selected from the groupconsisting of glucose, sucralose, trehalose, fructose, xylose, dextrose,galaxies, tagatose, maltose, sucrose, glycerol, dulcitol, mannitol,lactitol, sorbitol solution, xylitol, liquid maltitol, saccharine or thecorresponding sodium, potassium or calcium salt, cyclamate or thecorresponding sodium or calcium salt, aspartame, or acesulfame or thepotassium salt thereof, dulcin or ammonium glycyrrhizinate, alitame,linulin, lisomalt, neohesperidin dihydrochalcone, thaumatin or anycombination thereof; about 0.01% w/v to about 5% w/v of a flavoringagent selected from the group consisting of synthetic flavor oils andflavoring aromatics and/or natural oils, extracts from plant leaves,flowers, fruits, cinnamon oil, oil of wintergreen, peppermint oils,clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil,oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil, citrusoil, vanilla, lemon, orange, grape, lime, grapefruit flavors, apple,banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple,apricot essences or any combination thereof; 0% w/v to about 10% w/v ofan anti-foaming agent selected from the group consisting of simethicone,organic phosphates, alcohols, paraffin oils, stearates, glycols or anycombination thereof; 0% w/v to about 10% w/v of a surfactant selectedfrom the group consisting of sodium lauryl sulfite, docusate sodium,cocamidopropyl amino betaine, polyoxyethylene sorbitan fatty acid esters(polysorbate, Tween®), polyoxyethylene 15 hydroxystearate (macrogol 15hydroxystearate, Solutol HSI15)), polyoxyethylene castor oil derivatives(Cremophor® EL, ELP, RH 40), polyoxyethylene stearates (Myrj®), sorbitanfatty acid esters (Span®), polyoxyethylene alkyl ethers (Brij®,polyoxyethylene nonylphenol ether (Nonoxynol® or any combinationthereof; 0% w/v to about 10% w/v of an anti-oxidant selected from thegroup consisting of α-tocopherol acetate, ascorbic acid, erythorbicacid, butylated hydroxytoluene (BHT), d-α-tocopherol natural,monothioglycerol, sodium bisulfite, sodium sulfite, sodiummetabisulfite, potassium metabisulfite, acetone sodium bisulfite,ascorbyl palmitate, cysteine, d-α-tocopherol synthetic,nordihydroguaiaretic acid, sodium formaldehyde sulfoxylate, sodiumthiosulfate, acetylcysteine, ascorbyl palmitate, butylatedhydroxyanisole (BHA), cysteine hydrochloride, dithiothreitol, propylgallate, thiourea or any combination thereof; and 0% w/v to about 10%w/v of a preservative selected from the group consisting of ethanol,chlorobutanol, phenoxyethanol, potassium benzoate, benzyl alcohol,benzoic acid, potassium sorbate, sorbic acid, benzalkonium chloride,benzethonium chloride, cetrimonium bromide, cetylpyridinium chloride,bronopol, chlorbutol, chlorocresol, cresol, butylparaben or saltthereof, methylparaben or salt thereof, propylparaben or salt thereof,ethylparaben or salt thereof, phenol, thymol, phenylethanol, sodiumbenzoate, propylene glycol, glycerin, ghloroform or any combinationthereof.
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 65. The liquid dosage formof claim 41, wherein the pH is from about 4.0 to about 9.0. 66.(canceled)
 67. The liquid dosage form of claim 41, wherein the vehicleis selected from the group consisting of water, medium chaintriglyceride and combination thereof.
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 69. The liquiddosage form of claim 41 is ready to use oral suspension.
 70. The liquiddosage form of claim 41 is stable liquid dosage form characterized inthat any individual impurity present in the liquid dosage form is notmore than 2.0% and the total impurities present in the liquid dosageform are not more than 5.0%.
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 73. Theliquid dosage form of claim 41, wherein the dosage form has: (a) aC_(max) for imatinib, or a salt thereof, when assayed in the plasma of amammalian subject following administration that is at least about 70% toabout 143% greater than the C_(max) for an imatinib marketed or knownformulation, administered at the same dose; (b) an AUC for imatinib, ora salt thereof, when assayed in the plasma of a mammalian subjectfollowing administration that is at least about 80% to about 125%greater than the AUC for an imatinib marketed or known formulation,administered at the same dose; (c) a T_(max) for imatinib, or a saltthereof, when assayed in the plasma of a mammalian subject followingadministration that is less than about 6 hours to about 8 hours; or (d)any combination of (a), (b), and (c).
 74. The liquid dosage form ofclaim 41 is packaged in the pharmaceutically acceptable packagingmaterial selected from the group comprising of containers, pumps,bottles with spray pump, bottles with dropper assembly, bottles,collapsible tubes, glass ampoules, stoppered vials, pre-filled syringes,wherein the bottles and containers are clear or transparent or opaque oramber colored glass bottles and containers or clear or transparent oropaque or amber colored plastic bottles and containers made frompolyethylene, low-density polyethylene, high-density polyethylene,polyamide, polyolefin, polycarbonate, acrylic multipolymers,polypropylene, polyethylene terephthalate, polyvinyl chloride,polystyrene.
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